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Gene Information
Gene symbol: RPS6KB1
Gene name: ribosomal protein S6 kinase, 70kDa, polypeptide 1
HGNC ID: 10436
Synonyms: S6K1, p70(S6K)-alpha, PS6K
Related Genes
Related Sentences
| # | PMID | Sentence |
| 1 | 1380182 | Rapamycin, but not its structural analog FK506, also inhibited the basal and insulin-stimulated activity of the p70 ribosomal protein S6 kinase. |
| 2 | 1380182 | By contrast, insulin stimulation of the p85 Rsk S6 kinase and mitogen-activated protein (MAP) kinase activity were unaffected by drug. |
| 3 | 1380182 | Thus, rapamycin inhibits a signal transduction element that is necessary for the activation of p70 S6 kinase and mitogenesis but unnecessary for activation of p85 Rsk S6 kinase or MAP kinase. |
| 4 | 1737788 | An array of insulin-activated, proline-directed serine/threonine protein kinases phosphorylate the p70 S6 kinase. |
| 5 | 1737788 | This study characterizes the insulin-activated serine/threonine protein kinases in H4 hepatoma cells active on a 37-residue synthetic peptide (called the SKAIPS peptide) corresponding to a putative autoinhibitory domain in the carboxyl-terminal tail of the p70 S6 kinase as well as on recombinant p70 S6 kinase. |
| 6 | 1737788 | Three peaks of insulin-stimulated protein kinase active on both these substrates are identified as two (possibly three) isoforms of the 40-45-kDa erk/microtubule-associated protein (MAP)-2 kinase family and a 150-kDa form of cdc2. |
| 7 | 1737788 | Although distinguishable in their substrate specificity, these protein kinases together with the p54 MAP-2 kinase share a major common specificity determinant reflected in the SKAIPS peptide: the requirement for a proline residue immediately carboxyl-terminal to the site of Ser/Thr phosphorylation. |
| 8 | 1737788 | In addition, however, at least one peak of insulin-stimulated protein kinase active on recombinant p70, but not on the SKAIPS peptide, is present although not yet identified. |
| 9 | 1737788 | MFP/cdc2 phosphorylates both rat liver p70 S6 kinase and recombinant p70 S6 kinase exclusively at a set of Ser/Thr residues within the putative autoinhibitory (SKAIPS peptide) domain. erk/MAP kinase does not phosphorylate rat liver p70 S6 kinase, but readily phosphorylates recombinant p70 S6 kinase at sites both within and in addition to those encompassed by the SKAIPS peptide sequences. |
| 10 | 1737788 | Although the tryptic 32P-peptides bearing the cdc2 and erk/MAP kinase phosphorylation sites co-migrate with a subset of the sites phosphorylated in situ in insulin-stimulated cells, phosphorylation of the p70 S6 kinase by these proline-directed protein kinases in vitro does not reproducibly activate p70 S6 kinase activity. |
| 11 | 1737788 | Thus, one or more erk/MAP kinases and cdc2 are likely to participate in the insulin-induced phosphorylation of the p70 S6 kinase. |
| 12 | 1737788 | In addition to these kinases, however, phosphorylation of the p70 S6 kinase by other as yet unidentified protein kinases is necessary to recapitulate the multisite phosphorylation required for activation of the p70 S6 kinase. |
| 13 | 1737788 | An array of insulin-activated, proline-directed serine/threonine protein kinases phosphorylate the p70 S6 kinase. |
| 14 | 1737788 | This study characterizes the insulin-activated serine/threonine protein kinases in H4 hepatoma cells active on a 37-residue synthetic peptide (called the SKAIPS peptide) corresponding to a putative autoinhibitory domain in the carboxyl-terminal tail of the p70 S6 kinase as well as on recombinant p70 S6 kinase. |
| 15 | 1737788 | Three peaks of insulin-stimulated protein kinase active on both these substrates are identified as two (possibly three) isoforms of the 40-45-kDa erk/microtubule-associated protein (MAP)-2 kinase family and a 150-kDa form of cdc2. |
| 16 | 1737788 | Although distinguishable in their substrate specificity, these protein kinases together with the p54 MAP-2 kinase share a major common specificity determinant reflected in the SKAIPS peptide: the requirement for a proline residue immediately carboxyl-terminal to the site of Ser/Thr phosphorylation. |
| 17 | 1737788 | In addition, however, at least one peak of insulin-stimulated protein kinase active on recombinant p70, but not on the SKAIPS peptide, is present although not yet identified. |
| 18 | 1737788 | MFP/cdc2 phosphorylates both rat liver p70 S6 kinase and recombinant p70 S6 kinase exclusively at a set of Ser/Thr residues within the putative autoinhibitory (SKAIPS peptide) domain. erk/MAP kinase does not phosphorylate rat liver p70 S6 kinase, but readily phosphorylates recombinant p70 S6 kinase at sites both within and in addition to those encompassed by the SKAIPS peptide sequences. |
| 19 | 1737788 | Although the tryptic 32P-peptides bearing the cdc2 and erk/MAP kinase phosphorylation sites co-migrate with a subset of the sites phosphorylated in situ in insulin-stimulated cells, phosphorylation of the p70 S6 kinase by these proline-directed protein kinases in vitro does not reproducibly activate p70 S6 kinase activity. |
| 20 | 1737788 | Thus, one or more erk/MAP kinases and cdc2 are likely to participate in the insulin-induced phosphorylation of the p70 S6 kinase. |
| 21 | 1737788 | In addition to these kinases, however, phosphorylation of the p70 S6 kinase by other as yet unidentified protein kinases is necessary to recapitulate the multisite phosphorylation required for activation of the p70 S6 kinase. |
| 22 | 1737788 | An array of insulin-activated, proline-directed serine/threonine protein kinases phosphorylate the p70 S6 kinase. |
| 23 | 1737788 | This study characterizes the insulin-activated serine/threonine protein kinases in H4 hepatoma cells active on a 37-residue synthetic peptide (called the SKAIPS peptide) corresponding to a putative autoinhibitory domain in the carboxyl-terminal tail of the p70 S6 kinase as well as on recombinant p70 S6 kinase. |
| 24 | 1737788 | Three peaks of insulin-stimulated protein kinase active on both these substrates are identified as two (possibly three) isoforms of the 40-45-kDa erk/microtubule-associated protein (MAP)-2 kinase family and a 150-kDa form of cdc2. |
| 25 | 1737788 | Although distinguishable in their substrate specificity, these protein kinases together with the p54 MAP-2 kinase share a major common specificity determinant reflected in the SKAIPS peptide: the requirement for a proline residue immediately carboxyl-terminal to the site of Ser/Thr phosphorylation. |
| 26 | 1737788 | In addition, however, at least one peak of insulin-stimulated protein kinase active on recombinant p70, but not on the SKAIPS peptide, is present although not yet identified. |
| 27 | 1737788 | MFP/cdc2 phosphorylates both rat liver p70 S6 kinase and recombinant p70 S6 kinase exclusively at a set of Ser/Thr residues within the putative autoinhibitory (SKAIPS peptide) domain. erk/MAP kinase does not phosphorylate rat liver p70 S6 kinase, but readily phosphorylates recombinant p70 S6 kinase at sites both within and in addition to those encompassed by the SKAIPS peptide sequences. |
| 28 | 1737788 | Although the tryptic 32P-peptides bearing the cdc2 and erk/MAP kinase phosphorylation sites co-migrate with a subset of the sites phosphorylated in situ in insulin-stimulated cells, phosphorylation of the p70 S6 kinase by these proline-directed protein kinases in vitro does not reproducibly activate p70 S6 kinase activity. |
| 29 | 1737788 | Thus, one or more erk/MAP kinases and cdc2 are likely to participate in the insulin-induced phosphorylation of the p70 S6 kinase. |
| 30 | 1737788 | In addition to these kinases, however, phosphorylation of the p70 S6 kinase by other as yet unidentified protein kinases is necessary to recapitulate the multisite phosphorylation required for activation of the p70 S6 kinase. |
| 31 | 1737788 | An array of insulin-activated, proline-directed serine/threonine protein kinases phosphorylate the p70 S6 kinase. |
| 32 | 1737788 | This study characterizes the insulin-activated serine/threonine protein kinases in H4 hepatoma cells active on a 37-residue synthetic peptide (called the SKAIPS peptide) corresponding to a putative autoinhibitory domain in the carboxyl-terminal tail of the p70 S6 kinase as well as on recombinant p70 S6 kinase. |
| 33 | 1737788 | Three peaks of insulin-stimulated protein kinase active on both these substrates are identified as two (possibly three) isoforms of the 40-45-kDa erk/microtubule-associated protein (MAP)-2 kinase family and a 150-kDa form of cdc2. |
| 34 | 1737788 | Although distinguishable in their substrate specificity, these protein kinases together with the p54 MAP-2 kinase share a major common specificity determinant reflected in the SKAIPS peptide: the requirement for a proline residue immediately carboxyl-terminal to the site of Ser/Thr phosphorylation. |
| 35 | 1737788 | In addition, however, at least one peak of insulin-stimulated protein kinase active on recombinant p70, but not on the SKAIPS peptide, is present although not yet identified. |
| 36 | 1737788 | MFP/cdc2 phosphorylates both rat liver p70 S6 kinase and recombinant p70 S6 kinase exclusively at a set of Ser/Thr residues within the putative autoinhibitory (SKAIPS peptide) domain. erk/MAP kinase does not phosphorylate rat liver p70 S6 kinase, but readily phosphorylates recombinant p70 S6 kinase at sites both within and in addition to those encompassed by the SKAIPS peptide sequences. |
| 37 | 1737788 | Although the tryptic 32P-peptides bearing the cdc2 and erk/MAP kinase phosphorylation sites co-migrate with a subset of the sites phosphorylated in situ in insulin-stimulated cells, phosphorylation of the p70 S6 kinase by these proline-directed protein kinases in vitro does not reproducibly activate p70 S6 kinase activity. |
| 38 | 1737788 | Thus, one or more erk/MAP kinases and cdc2 are likely to participate in the insulin-induced phosphorylation of the p70 S6 kinase. |
| 39 | 1737788 | In addition to these kinases, however, phosphorylation of the p70 S6 kinase by other as yet unidentified protein kinases is necessary to recapitulate the multisite phosphorylation required for activation of the p70 S6 kinase. |
| 40 | 1737788 | An array of insulin-activated, proline-directed serine/threonine protein kinases phosphorylate the p70 S6 kinase. |
| 41 | 1737788 | This study characterizes the insulin-activated serine/threonine protein kinases in H4 hepatoma cells active on a 37-residue synthetic peptide (called the SKAIPS peptide) corresponding to a putative autoinhibitory domain in the carboxyl-terminal tail of the p70 S6 kinase as well as on recombinant p70 S6 kinase. |
| 42 | 1737788 | Three peaks of insulin-stimulated protein kinase active on both these substrates are identified as two (possibly three) isoforms of the 40-45-kDa erk/microtubule-associated protein (MAP)-2 kinase family and a 150-kDa form of cdc2. |
| 43 | 1737788 | Although distinguishable in their substrate specificity, these protein kinases together with the p54 MAP-2 kinase share a major common specificity determinant reflected in the SKAIPS peptide: the requirement for a proline residue immediately carboxyl-terminal to the site of Ser/Thr phosphorylation. |
| 44 | 1737788 | In addition, however, at least one peak of insulin-stimulated protein kinase active on recombinant p70, but not on the SKAIPS peptide, is present although not yet identified. |
| 45 | 1737788 | MFP/cdc2 phosphorylates both rat liver p70 S6 kinase and recombinant p70 S6 kinase exclusively at a set of Ser/Thr residues within the putative autoinhibitory (SKAIPS peptide) domain. erk/MAP kinase does not phosphorylate rat liver p70 S6 kinase, but readily phosphorylates recombinant p70 S6 kinase at sites both within and in addition to those encompassed by the SKAIPS peptide sequences. |
| 46 | 1737788 | Although the tryptic 32P-peptides bearing the cdc2 and erk/MAP kinase phosphorylation sites co-migrate with a subset of the sites phosphorylated in situ in insulin-stimulated cells, phosphorylation of the p70 S6 kinase by these proline-directed protein kinases in vitro does not reproducibly activate p70 S6 kinase activity. |
| 47 | 1737788 | Thus, one or more erk/MAP kinases and cdc2 are likely to participate in the insulin-induced phosphorylation of the p70 S6 kinase. |
| 48 | 1737788 | In addition to these kinases, however, phosphorylation of the p70 S6 kinase by other as yet unidentified protein kinases is necessary to recapitulate the multisite phosphorylation required for activation of the p70 S6 kinase. |
| 49 | 1737788 | An array of insulin-activated, proline-directed serine/threonine protein kinases phosphorylate the p70 S6 kinase. |
| 50 | 1737788 | This study characterizes the insulin-activated serine/threonine protein kinases in H4 hepatoma cells active on a 37-residue synthetic peptide (called the SKAIPS peptide) corresponding to a putative autoinhibitory domain in the carboxyl-terminal tail of the p70 S6 kinase as well as on recombinant p70 S6 kinase. |
| 51 | 1737788 | Three peaks of insulin-stimulated protein kinase active on both these substrates are identified as two (possibly three) isoforms of the 40-45-kDa erk/microtubule-associated protein (MAP)-2 kinase family and a 150-kDa form of cdc2. |
| 52 | 1737788 | Although distinguishable in their substrate specificity, these protein kinases together with the p54 MAP-2 kinase share a major common specificity determinant reflected in the SKAIPS peptide: the requirement for a proline residue immediately carboxyl-terminal to the site of Ser/Thr phosphorylation. |
| 53 | 1737788 | In addition, however, at least one peak of insulin-stimulated protein kinase active on recombinant p70, but not on the SKAIPS peptide, is present although not yet identified. |
| 54 | 1737788 | MFP/cdc2 phosphorylates both rat liver p70 S6 kinase and recombinant p70 S6 kinase exclusively at a set of Ser/Thr residues within the putative autoinhibitory (SKAIPS peptide) domain. erk/MAP kinase does not phosphorylate rat liver p70 S6 kinase, but readily phosphorylates recombinant p70 S6 kinase at sites both within and in addition to those encompassed by the SKAIPS peptide sequences. |
| 55 | 1737788 | Although the tryptic 32P-peptides bearing the cdc2 and erk/MAP kinase phosphorylation sites co-migrate with a subset of the sites phosphorylated in situ in insulin-stimulated cells, phosphorylation of the p70 S6 kinase by these proline-directed protein kinases in vitro does not reproducibly activate p70 S6 kinase activity. |
| 56 | 1737788 | Thus, one or more erk/MAP kinases and cdc2 are likely to participate in the insulin-induced phosphorylation of the p70 S6 kinase. |
| 57 | 1737788 | In addition to these kinases, however, phosphorylation of the p70 S6 kinase by other as yet unidentified protein kinases is necessary to recapitulate the multisite phosphorylation required for activation of the p70 S6 kinase. |
| 58 | 1909327 | Insulin-activated protein kinases phosphorylate a pseudosubstrate synthetic peptide inhibitor of the p70 S6 kinase. |
| 59 | 1909327 | p70 S6 kinase, a major insulin-mitogen-activated ribosomal S6 protein kinase in mammalian cells, is activated by phosphorylation of multiple Ser/Thr residues on the enzyme polypeptide. |
| 60 | 1909327 | Insulin-activated protein kinases phosphorylate a pseudosubstrate synthetic peptide inhibitor of the p70 S6 kinase. |
| 61 | 1909327 | p70 S6 kinase, a major insulin-mitogen-activated ribosomal S6 protein kinase in mammalian cells, is activated by phosphorylation of multiple Ser/Thr residues on the enzyme polypeptide. |
| 62 | 2236064 | Outside of this segment of approximately 330 amino acids, the structures of the p70 and p85 S6 kinases diverge substantially. |
| 63 | 2236064 | The p70 S6 kinase is known to be activated through serine/threonine phosphorylation by unidentified insulin/mitogen-activated protein kinases. |
| 64 | 2236064 | This motif may prevent autophosphorylation but permit transphosphorylation; two of these serine residues reside in a maturation promoting factor (MPF)/cdc-2 consensus motif. |
| 65 | 2236064 | Thus, hormonal regulation of S6 kinase may involve the action of MPF/cdc-2 or protein kinases with related substrate specificity. |
| 66 | 7777579 | Phosphatidylinositol 3-kinase signals activation of p70 S6 kinase in situ through site-specific p70 phosphorylation. |
| 67 | 7777579 | The p70 S6 kinase is activated by insulin and mitogens through multisite phosphorylation of the enzyme. |
| 68 | 7777579 | Phosphatidylinositol 3-kinase signals activation of p70 S6 kinase in situ through site-specific p70 phosphorylation. |
| 69 | 7777579 | The p70 S6 kinase is activated by insulin and mitogens through multisite phosphorylation of the enzyme. |
| 70 | 8754813 | Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) by the activated receptors for insulin, IGF-1, and various cytokines creates binding sites for signaling proteins with Src homology 2 domains (SH2 proteins). |
| 71 | 8754813 | Determining the role of specific SH2 proteins during insulin signaling has been difficult because IRS-1 possesses as many as 18 potential tyrosine phosphorylation sites, several of which contain redundant motifs. |
| 72 | 8754813 | Using 32D cells, which contain no endogenous IRS proteins, we compared the signaling ability of an IRS-1 molecule in which 18 potential tyrosine phosphorylation sites were replaced by phenylalanine (IRS-1(F18)) with two derivative molecules which retained three YMXM motifs (IRS-1(3YMXM)) or the two COOH-terminal SHP2-Fyn binding sites (IRS-1(YCT)). |
| 73 | 8754813 | During insulin stimulation, IRS-1(F18) failed to undergo tyrosine phosphorylation or mediate activation of the phosphotidylinositol (PI) 3'-kinase or p70(s6k); IRS-1(YCT) was tyrosine phosphorylated but also failed to mediate these signaling events. |
| 74 | 8754813 | IRS-1(F18) and IRS-1(YCT) partially mediated similar levels of insulin-stimulated mitogenesis at high insulin concentrations, however, suggesting that IRS-1 contains phosphotyrosine-independent elements which effect mitogenic signals, and that the sites in IRS-l(YCT) do not augment this signal. |
| 75 | 8754813 | IRS-1(3YMXM) mediated the maximal mitogenic response to insulin, although the response to insulin was more sensitive with wild-type IRS-1. |
| 76 | 8754813 | By contrast, the association of IRS-1(3YMXM) with PI 3'-kinase was more sensitive to insulin than the association with IRS-1. |
| 77 | 8798677 | The pleckstrin homology domain is the principal link between the insulin receptor and IRS-1. |
| 78 | 8798677 | Interaction domains located in the NH2 terminus of IRS-1 mediate its recognition by the insulin receptor. |
| 79 | 8798677 | Alignment of IRS-1 and IRS-2 reveals two homology regions: the IH1(PH) contains a pleckstrin homology (PH) domain, and the IH2(PTB) contains a phosphotyrosine binding (PTB) domain. |
| 80 | 8798677 | Peptide competition experiments demonstrated that the IH2(PTB) in IRS-2, like the corresponding domain in IRS-1, binds directly to peptides containing NPXY motifs. |
| 81 | 8798677 | In 32D cells the IH1(PH) was essential for insulin-stimulated tyrosine phosphorylation of IRS-1 and insulin-stimulated phosphatidylinositol 3-kinase activity and p70(s6k) phosphorylation. |
| 82 | 8798677 | In contrast, the IH2(PTB) and the SAIN regions were not required for these insulin actions; however, the IH2(PTB) improved the coupling between IRS-1 and the insulin receptor. |
| 83 | 8798677 | Overexpression of the insulin receptor in 32DIR cells increased IRS-1 tyrosine phosphorylation and mediated insulin-stimulated DNA synthesis. |
| 84 | 8798677 | Thus, the PH and PTB domains equally couple IRS-1 to high levels of insulin receptor normally expressed in most cells, whereas at low levels of insulin receptors the PTB domain is inefficient and the PH domain is essential for a productive interaction. |
| 85 | 8910437 | We have reported previously that substitution of the transmembrane domain of the insulin receptor with that of the erbB-2 oncogene (IRerbV-->E) results in constitutive activation of the insulin receptor kinase. |
| 86 | 8910437 | Compared to NIH3T3 cells overexpressing wild-type insulin receptors (IRwt), cells overexpressing IRerbV-->E displayed a decrease in IRS-1 protein content by 55%, but basal tyrosine phosphorylation of IRS-1 was increased. |
| 87 | 8910437 | This resulted in an increased association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, increased phosphatidylinositol 3-kinase activity in anti-IRS-1 immunoprecipitates, constitutive activation of p70 S6 protein kinase, and an increased association of Grb2 with Shc in the absence of ligand. |
| 88 | 8910437 | However, Grb2 association with IRS-1 could not be detected in the basal or insulin-stimulated states, and mitogen-activated protein kinase (MAPK) activity could not be stimulated by insulin, epidermal growth factor, or platelet-derived growth factor. |
| 89 | 8910437 | With decreased IRS-1 content, tyrosine phosphorylation of IRS-1 was decreased by over 75%, leading to decreased IRS-1-associated PI 3-kinase and Grb2. |
| 90 | 8910437 | In addition, Grb2 association with Shc and activation of MAPK and the p70 S6 kinase were insensitive to insulin stimulation. |
| 91 | 8910437 | By contrast, association of Grb2 with Shc and activation of MAPK, but not the p70 S6 kinase, could be stimulated by epidermal growth factor or platelet-derived growth factor. |
| 92 | 8910437 | We have reported previously that substitution of the transmembrane domain of the insulin receptor with that of the erbB-2 oncogene (IRerbV-->E) results in constitutive activation of the insulin receptor kinase. |
| 93 | 8910437 | Compared to NIH3T3 cells overexpressing wild-type insulin receptors (IRwt), cells overexpressing IRerbV-->E displayed a decrease in IRS-1 protein content by 55%, but basal tyrosine phosphorylation of IRS-1 was increased. |
| 94 | 8910437 | This resulted in an increased association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, increased phosphatidylinositol 3-kinase activity in anti-IRS-1 immunoprecipitates, constitutive activation of p70 S6 protein kinase, and an increased association of Grb2 with Shc in the absence of ligand. |
| 95 | 8910437 | However, Grb2 association with IRS-1 could not be detected in the basal or insulin-stimulated states, and mitogen-activated protein kinase (MAPK) activity could not be stimulated by insulin, epidermal growth factor, or platelet-derived growth factor. |
| 96 | 8910437 | With decreased IRS-1 content, tyrosine phosphorylation of IRS-1 was decreased by over 75%, leading to decreased IRS-1-associated PI 3-kinase and Grb2. |
| 97 | 8910437 | In addition, Grb2 association with Shc and activation of MAPK and the p70 S6 kinase were insensitive to insulin stimulation. |
| 98 | 8910437 | By contrast, association of Grb2 with Shc and activation of MAPK, but not the p70 S6 kinase, could be stimulated by epidermal growth factor or platelet-derived growth factor. |
| 99 | 9175775 | Insulin stimulates p70 S6 kinase in the nucleus of cells. |
| 100 | 9175775 | Insulin action on both cytoplasmic and nuclear processes is dependent on activation of p70 S6 kinase (p70S6K). |
| 101 | 9175775 | Rapamycin, a selective inhibitor of p70S6K, and the casein kinase II inhibitor DRB blocked insulin-stimulated nuclear and cytosolic p70S6K. |
| 102 | 9175775 | Insulin stimulates p70 S6 kinase in the nucleus of cells. |
| 103 | 9175775 | Insulin action on both cytoplasmic and nuclear processes is dependent on activation of p70 S6 kinase (p70S6K). |
| 104 | 9175775 | Rapamycin, a selective inhibitor of p70S6K, and the casein kinase II inhibitor DRB blocked insulin-stimulated nuclear and cytosolic p70S6K. |
| 105 | 9334222 | Regulation of eIF-4E BP1 phosphorylation by mTOR. |
| 106 | 9334222 | The proteins eIF-4E BP1 and p70 S6 kinase each undergo an insulin/mitogen-stimulated phosphorylation in situ that is partially inhibited by rapamycin. |
| 107 | 9334222 | Previous work has established that the protein known as mTOR/RAFT-1/FRAP is the target through which the rapamycin.FKBP12 complex acts to dephosphorylate/deactivate the p70 S6 kinase; thus, some mTOR mutants that have lost the ability to bind to the rapamycin.FKBP12 complex in vitro can protect the p70 S6 kinase against rapamycin-induced dephosphorylation/deactivation in situ. |
| 108 | 9334222 | We show herein that such mTOR mutants also protect eIF-4E BP1 against rapamycin-induced dephosphorylation, and for both p70 S6 kinase and eIF-4E BP1, such protection requires that the rapamycin-resistant mTOR variant retains an active catalytic domain. |
| 109 | 9334222 | In contrast, mutants of p70 S6 kinase rendered intrinsically resistant to inhibition by rapamycin in situ are not able to protect coexpressed eIF-4E BP1 from rapamycin-induced dephosphorylation. |
| 110 | 9334222 | We conclude that mTOR is an upstream regulator of eIF-4E BP1 as well as the p70 S6 kinase; moreover, these two mTOR targets are regulated in a parallel rather than sequential manner. |
| 111 | 9334222 | Regulation of eIF-4E BP1 phosphorylation by mTOR. |
| 112 | 9334222 | The proteins eIF-4E BP1 and p70 S6 kinase each undergo an insulin/mitogen-stimulated phosphorylation in situ that is partially inhibited by rapamycin. |
| 113 | 9334222 | Previous work has established that the protein known as mTOR/RAFT-1/FRAP is the target through which the rapamycin.FKBP12 complex acts to dephosphorylate/deactivate the p70 S6 kinase; thus, some mTOR mutants that have lost the ability to bind to the rapamycin.FKBP12 complex in vitro can protect the p70 S6 kinase against rapamycin-induced dephosphorylation/deactivation in situ. |
| 114 | 9334222 | We show herein that such mTOR mutants also protect eIF-4E BP1 against rapamycin-induced dephosphorylation, and for both p70 S6 kinase and eIF-4E BP1, such protection requires that the rapamycin-resistant mTOR variant retains an active catalytic domain. |
| 115 | 9334222 | In contrast, mutants of p70 S6 kinase rendered intrinsically resistant to inhibition by rapamycin in situ are not able to protect coexpressed eIF-4E BP1 from rapamycin-induced dephosphorylation. |
| 116 | 9334222 | We conclude that mTOR is an upstream regulator of eIF-4E BP1 as well as the p70 S6 kinase; moreover, these two mTOR targets are regulated in a parallel rather than sequential manner. |
| 117 | 9334222 | Regulation of eIF-4E BP1 phosphorylation by mTOR. |
| 118 | 9334222 | The proteins eIF-4E BP1 and p70 S6 kinase each undergo an insulin/mitogen-stimulated phosphorylation in situ that is partially inhibited by rapamycin. |
| 119 | 9334222 | Previous work has established that the protein known as mTOR/RAFT-1/FRAP is the target through which the rapamycin.FKBP12 complex acts to dephosphorylate/deactivate the p70 S6 kinase; thus, some mTOR mutants that have lost the ability to bind to the rapamycin.FKBP12 complex in vitro can protect the p70 S6 kinase against rapamycin-induced dephosphorylation/deactivation in situ. |
| 120 | 9334222 | We show herein that such mTOR mutants also protect eIF-4E BP1 against rapamycin-induced dephosphorylation, and for both p70 S6 kinase and eIF-4E BP1, such protection requires that the rapamycin-resistant mTOR variant retains an active catalytic domain. |
| 121 | 9334222 | In contrast, mutants of p70 S6 kinase rendered intrinsically resistant to inhibition by rapamycin in situ are not able to protect coexpressed eIF-4E BP1 from rapamycin-induced dephosphorylation. |
| 122 | 9334222 | We conclude that mTOR is an upstream regulator of eIF-4E BP1 as well as the p70 S6 kinase; moreover, these two mTOR targets are regulated in a parallel rather than sequential manner. |
| 123 | 9334222 | Regulation of eIF-4E BP1 phosphorylation by mTOR. |
| 124 | 9334222 | The proteins eIF-4E BP1 and p70 S6 kinase each undergo an insulin/mitogen-stimulated phosphorylation in situ that is partially inhibited by rapamycin. |
| 125 | 9334222 | Previous work has established that the protein known as mTOR/RAFT-1/FRAP is the target through which the rapamycin.FKBP12 complex acts to dephosphorylate/deactivate the p70 S6 kinase; thus, some mTOR mutants that have lost the ability to bind to the rapamycin.FKBP12 complex in vitro can protect the p70 S6 kinase against rapamycin-induced dephosphorylation/deactivation in situ. |
| 126 | 9334222 | We show herein that such mTOR mutants also protect eIF-4E BP1 against rapamycin-induced dephosphorylation, and for both p70 S6 kinase and eIF-4E BP1, such protection requires that the rapamycin-resistant mTOR variant retains an active catalytic domain. |
| 127 | 9334222 | In contrast, mutants of p70 S6 kinase rendered intrinsically resistant to inhibition by rapamycin in situ are not able to protect coexpressed eIF-4E BP1 from rapamycin-induced dephosphorylation. |
| 128 | 9334222 | We conclude that mTOR is an upstream regulator of eIF-4E BP1 as well as the p70 S6 kinase; moreover, these two mTOR targets are regulated in a parallel rather than sequential manner. |
| 129 | 9334222 | Regulation of eIF-4E BP1 phosphorylation by mTOR. |
| 130 | 9334222 | The proteins eIF-4E BP1 and p70 S6 kinase each undergo an insulin/mitogen-stimulated phosphorylation in situ that is partially inhibited by rapamycin. |
| 131 | 9334222 | Previous work has established that the protein known as mTOR/RAFT-1/FRAP is the target through which the rapamycin.FKBP12 complex acts to dephosphorylate/deactivate the p70 S6 kinase; thus, some mTOR mutants that have lost the ability to bind to the rapamycin.FKBP12 complex in vitro can protect the p70 S6 kinase against rapamycin-induced dephosphorylation/deactivation in situ. |
| 132 | 9334222 | We show herein that such mTOR mutants also protect eIF-4E BP1 against rapamycin-induced dephosphorylation, and for both p70 S6 kinase and eIF-4E BP1, such protection requires that the rapamycin-resistant mTOR variant retains an active catalytic domain. |
| 133 | 9334222 | In contrast, mutants of p70 S6 kinase rendered intrinsically resistant to inhibition by rapamycin in situ are not able to protect coexpressed eIF-4E BP1 from rapamycin-induced dephosphorylation. |
| 134 | 9334222 | We conclude that mTOR is an upstream regulator of eIF-4E BP1 as well as the p70 S6 kinase; moreover, these two mTOR targets are regulated in a parallel rather than sequential manner. |
| 135 | 9389501 | Hepatic expression of ErbB3 is repressed by insulin in a pathway sensitive to PI-3 kinase inhibitors. |
| 136 | 9389501 | ErbB3 is an epidermal growth factor receptor-related type I tyrosine kinase receptor capable, in conjunction with ErbB2 or epidermal growth factor receptor, of transmitting proliferative and differentiative signals in a variety of cell types. |
| 137 | 9389501 | Insulin inhibits the increase in heregulin beta1 binding, as well as the increase in ErbB3 messenger RNA and protein. |
| 138 | 9389501 | Two models of insulin deficiency in vivo (diabetes and fasting) demonstrated elevated levels of hepatic ErbB3 protein, strengthening the relevance of our observations in vitro. |
| 139 | 9389501 | Using chemical activators or antagonists, we sought to identify the signaling pathways that link insulin to ErbB3 expression. |
| 140 | 9389501 | The PI-3 kinase inhibitors, wortmannin and LY294002, completely blocked the inhibition of ErbB3 protein expression by insulin, suggesting a role for PI-3 kinase in the regulation of this growth factor receptor. |
| 141 | 9389501 | Rapamycin, an inhibitor of p70 S6 kinase, an enzyme downstream of PI-3 kinase, failed to block the effect of insulin on ErbB3 expression. |
| 142 | 9389501 | These results suggest a complex regulatory paradign for ErbB3 that includes PI-3 kinase and may be linked, via insulin, to the metabolic status of the animal. |
| 143 | 9468528 | Insulin-like growth factor-I receptor internalization regulates signaling via the Shc/mitogen-activated protein kinase pathway, but not the insulin receptor substrate-1 pathway. |
| 144 | 9468528 | Insulin-like growth factor-I (IGF-I) receptors activate divergent signaling pathways by phosphorylating multiple cellular proteins, including insulin receptor substrate-1 (IRS-1) and the Shc proteins. |
| 145 | 9468528 | This study investigates the relationship between IGF-I receptor internalization and signaling via IRS-1 and Shc. |
| 146 | 9468528 | A mutation in the C terminus of the IGF-I receptor decreased both the rate of receptor internalization and IGF-I-stimulated Shc phosphorylation by more than 50%, but did not affect IRS-1 phosphorylation. |
| 147 | 9468528 | Low temperature (15 degrees C) decreased IGF-I receptor internalization and completely inhibited Shc phosphorylation. |
| 148 | 9468528 | Dansylcadaverine decreased receptor internalization and Shc phosphorylation, but did not change receptor or IRS-1 phosphorylation. |
| 149 | 9468528 | Consistent with these findings, dansylcadaverine inhibited IGF-I-stimulated Shc-Grb2 association, mitogen-activated protein kinase phosphorylation, and p90 ribosomal S6 kinase activation, but did not affect the association of phosphatidylinositide 3-kinase with IRS-1 or activation of p70 S6 kinase. |
| 150 | 9468528 | These data support the concept that Shc/mitogen-activated protein kinase pathway activation requires IGF-I receptor internalization, whereas the IRS-1 pathway is activated by both cell surface and endosomal receptors. |
| 151 | 9525995 | Exposure of cells to high physiologic concentrations of amino acids activates intermediates important in the initiation of protein synthesis, including p70 S6 kinase and PHAS-I, in synergy with insulin. |
| 152 | 9525995 | Concurrently, amino acids inhibit early steps in insulin action critical for glucose transport and inhibition of gluconeogenesis, including decreased insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-2, decreased binding of grb 2 and the p85 subunit of phosphatidylinositol 3-kinase to IRS-1 and IRS-2, and a marked inhibition of insulin-stimulated phosphatidylinositol 3-kinase. |
| 153 | 9593725 | Association of the insulin receptor with phospholipase C-gamma (PLCgamma) in 3T3-L1 adipocytes suggests a role for PLCgamma in metabolic signaling by insulin. |
| 154 | 9593725 | Phospholipase C-gamma (PLCgamma) is the isozyme of PLC phosphorylated by multiple tyrosine kinases including epidermal growth factor, platelet-derived growth factor, nerve growth factor receptors, and nonreceptor tyrosine kinases. |
| 155 | 9593725 | To determine the functional significance of the interaction of PLCgamma and the IR, we used a specific inhibitor of PLC, U73122, or microinjection of SH2 domain glutathione S-transferase fusion proteins derived from PLCgamma to block insulin-stimulated GLUT4 translocation. |
| 156 | 9593725 | U73122 selectively inhibits mitogen-activated protein kinase, leaving the Akt and p70 S6 kinase pathways unperturbed. |
| 157 | 9651378 | Insulin-like growth factor I (IGF-I)-stimulated pancreatic beta-cell growth is glucose-dependent. |
| 158 | 9651378 | Synergistic activation of insulin receptor substrate-mediated signal transduction pathways by glucose and IGF-I in INS-1 cells. |
| 159 | 9651378 | Insulin-like growth factor I (IGF-I)-induced INS-1 cell proliferation was glucose-dependent only in the physiologically relevant concentration range (6-18 mM glucose). |
| 160 | 9651378 | Glucose metabolism and phosphatidylinositol 3'-kinase (PI 3'-kinase) activation were necessary for both glucose and IGF-I-stimulated INS-1 cell proliferation. |
| 161 | 9651378 | IGF-I and 15 mM glucose increased tyrosine phosphorylation mediated recruitment of Grb2/mSOS and PI 3'-kinase to IRS-2 and pp60. |
| 162 | 9651378 | Glucose and IGF-I also induced Shc association with Grb2/mSOS. |
| 163 | 9651378 | In contrast, p70(S6K) was activated with increasing glucose concentration (between 6 and 18 mM), and potentiated by IGF-I in the same glucose concentration range which correlated with INS-1 cell proliferation rate. |
| 164 | 9651378 | Thus, glucose and IGF-I-induced beta-cell proliferation were mediated via a signaling mechanism that was facilitated by mitogen-activated protein kinase but dependent on IRS-mediated induction of PI 3'-kinase activity and downstream activation of p70(S6K). |
| 165 | 9651378 | The glucose dependence of IGF-I mediated INS-1 cell proliferation emphasizes beta-cell signaling mechanisms are rather unique in being tightly linked to glycolytic metabolic flux. |
| 166 | 9651378 | Insulin-like growth factor I (IGF-I)-stimulated pancreatic beta-cell growth is glucose-dependent. |
| 167 | 9651378 | Synergistic activation of insulin receptor substrate-mediated signal transduction pathways by glucose and IGF-I in INS-1 cells. |
| 168 | 9651378 | Insulin-like growth factor I (IGF-I)-induced INS-1 cell proliferation was glucose-dependent only in the physiologically relevant concentration range (6-18 mM glucose). |
| 169 | 9651378 | Glucose metabolism and phosphatidylinositol 3'-kinase (PI 3'-kinase) activation were necessary for both glucose and IGF-I-stimulated INS-1 cell proliferation. |
| 170 | 9651378 | IGF-I and 15 mM glucose increased tyrosine phosphorylation mediated recruitment of Grb2/mSOS and PI 3'-kinase to IRS-2 and pp60. |
| 171 | 9651378 | Glucose and IGF-I also induced Shc association with Grb2/mSOS. |
| 172 | 9651378 | In contrast, p70(S6K) was activated with increasing glucose concentration (between 6 and 18 mM), and potentiated by IGF-I in the same glucose concentration range which correlated with INS-1 cell proliferation rate. |
| 173 | 9651378 | Thus, glucose and IGF-I-induced beta-cell proliferation were mediated via a signaling mechanism that was facilitated by mitogen-activated protein kinase but dependent on IRS-mediated induction of PI 3'-kinase activity and downstream activation of p70(S6K). |
| 174 | 9651378 | The glucose dependence of IGF-I mediated INS-1 cell proliferation emphasizes beta-cell signaling mechanisms are rather unique in being tightly linked to glycolytic metabolic flux. |
| 175 | 9660977 | Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways. |
| 176 | 9660977 | We show that secreted insulin acts via beta-cell insulin receptors and up-regulates insulin gene transcription by signaling through the IRS-2/PI-3 kinase/p70 s6k and CaM kinase pathways. |
| 177 | 9660977 | Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways. |
| 178 | 9660977 | We show that secreted insulin acts via beta-cell insulin receptors and up-regulates insulin gene transcription by signaling through the IRS-2/PI-3 kinase/p70 s6k and CaM kinase pathways. |
| 179 | 9721171 | Regulation of protein synthesis by cholecystokinin in rat pancreatic acini involves PHAS-I and the p70 S6 kinase pathway. |
| 180 | 9836529 | Expression and regulation of neuronal apoptosis inhibitory protein during adipocyte differentiation. |
| 181 | 9836529 | We have used the 3T3-L1 and 3T3-F442A preadipocyte cell lines to examine the expression and regulation of neuronal apoptosis inhibitory protein (NAIP) during adipocyte differentiation. |
| 182 | 9836529 | In 3T3-L1 cells, the increase in NAIP occurred by day 4 of the 8-day differentiation protocol, which includes exposure of confluent preadipocytes to insulin, dexamethasone, and isobutylmethylxanthine. |
| 183 | 9836529 | Addition of rapamycin, a p70 S6 kinase inhibitor that blocks adipocyte differentiation, to the 3T3-L1 differentiation medium prevented the rise in NAIP expression. |
| 184 | 9836529 | These data demonstrate for the first time that NAIP is expressed in adipocyte cell lines and primary adipocytes. |
| 185 | 9854185 | In the present study, we have investigated the diabetes-associated alterations in the insulin signalling cascade, especially the phosphatidylinositol-3 kinase (PI-3 kinase)/p70 S6 kinase (p70(S6K)) pathway, in rat skeletal muscle. |
| 186 | 9854185 | LY 294002, a specific inhibitor of PI-3 kinase, markedly decreased the basal rate of protein synthesis and completely prevented insulin-mediated stimulation of this process both in control and diabetic rats. |
| 187 | 9854185 | Thus, PI-3 kinase is required for insulin-stimulated muscle protein synthesis in diabetic rats as in the controls. |
| 188 | 9854185 | Neither basal nor insulin-stimulated p70(S6K) activity, a signalling element lying downstream of mTOR, were modified by STZ-diabetes. |
| 189 | 9854185 | In the present study, we have investigated the diabetes-associated alterations in the insulin signalling cascade, especially the phosphatidylinositol-3 kinase (PI-3 kinase)/p70 S6 kinase (p70(S6K)) pathway, in rat skeletal muscle. |
| 190 | 9854185 | LY 294002, a specific inhibitor of PI-3 kinase, markedly decreased the basal rate of protein synthesis and completely prevented insulin-mediated stimulation of this process both in control and diabetic rats. |
| 191 | 9854185 | Thus, PI-3 kinase is required for insulin-stimulated muscle protein synthesis in diabetic rats as in the controls. |
| 192 | 9854185 | Neither basal nor insulin-stimulated p70(S6K) activity, a signalling element lying downstream of mTOR, were modified by STZ-diabetes. |
| 193 | 9886813 | Mixed hindlimb skeletal muscle lysates were used to determine the expression and enzymatic activities of the extracellular regulated kinase 2 (ERK2), p90 ribosomal S6 kinase (RSK2), Akt, and p70 S6 kinase (p70S6k). |
| 194 | 9886813 | In all three groups of rats, insulin significantly increased ERK2, RSK2, Akt, and p70S6k activities. |
| 195 | 9886813 | There was no effect of diabetes on insulin-stimulated ERK2 activity or ERK2 protein levels. |
| 196 | 9886813 | RSK2 expression and insulin-stimulated RSK2 activity were significantly elevated in diabetic rats compared with those in the control animals. |
| 197 | 9886813 | Insulin-stimulated Akt activity was also significantly greater in the diabetic animals, but there was no change in protein expression. |
| 198 | 9886813 | Islet transplantation partially (RSK2) or fully (Akt, p70S6k) normalized these diabetes-induced changes in insulin signaling proteins. |
| 199 | 10021376 | Phosphoinositide-dependent kinase 1 (PDK1) is at the hub of many signalling pathways, activating PKB and PKC isoenzymes, as well as p70 S6 kinase and perhaps PKA. |
| 200 | 10102683 | Activation of protein kinase B and induction of adipogenesis by insulin in 3T3-L1 preadipocytes: contribution of phosphoinositide-3,4,5-trisphosphate versus phosphoinositide-3,4-bisphosphate. |
| 201 | 10102683 | PKB was also activated by insulin, in a dose- and time-dependent manner. |
| 202 | 10102683 | Wortmannin and LY294002, inhibitors of PI 3-kinase, reduced insulin-dependent activation of PKB, whereas rapamycin, an inhibitor of p70 S6 kinase, had no effect. |
| 203 | 10102683 | Platelet-derived growth factor (PDGF), which is not adipogenic, stimulated the production of both 3-phosphorylated phosphoinositide species, and this was associated with a greater activation of PKB than that observed with insulin. |
| 204 | 10102683 | A low dose of PDGF (1 ng/ml), which increased the production of only PI(3,4,5)P3 and mirrored the insulin effect, was unable to induce adipocyte differentiation. |
| 205 | 10102683 | In summary, insulin and PDGF differ with respect to the accumulation of 3-phosphorylated phosphoinositides and to PKB activation in 3T3-L1 preadipocytes, but these responses do not themselves explain why insulin, but not PDGF, is adipogenic. |
| 206 | 10318852 | Membrane-targeted phosphatidylinositol 3-kinase mimics insulin actions and induces a state of cellular insulin resistance. |
| 207 | 10318852 | Even at this submaximal PI 3-kinase activity, p110(CAAX) fully stimulated p70 S6 kinase, Akt, 2-deoxyglucose uptake, and Ras, whereas, p110(WT) had little or no effect on these downstream effects. |
| 208 | 10318852 | Interestingly p110(CAAX) did not activate MAP kinase, despite its stimulation of p21(ras). |
| 209 | 10318852 | Surprisingly, p110(CAAX) did not increase basal glycogen synthase activity, and inhibited insulin stimulated activity, indicative of cellular resistance to this action of insulin. p110(CAAX) also inhibited insulin stimulated, but not platelet-derived growth factor-stimulated mitogen-activated protein kinase phosphorylation, demonstrating that the p110(CAAX) induced inhibition of mitogen-activated protein kinase and insulin signaling is specific, and not due to some toxic or nonspecific effect on the cells. |
| 210 | 10318852 | Moreover, p110(CAAX) stimulated IRS-1 Ser/Thr phosphorylation, and inhibited IRS-1 associated PI 3-kinase activity, without affecting insulin receptor tyrosine phosphorylation, suggesting that it may play an important role as a negative regulator for insulin signaling. |
| 211 | 10329981 | Differential regulation of MAP kinase, p70(S6K), and Akt by contraction and insulin in rat skeletal muscle. |
| 212 | 10329981 | To study the effects of contractile activity on mitogen-activated protein kinase (MAP kinase), p70 S6 kinase (p70(S6K)), and Akt kinase signaling in rat skeletal muscle, hindlimb muscles were contracted by electrical stimulation of the sciatic nerve for periods of 15 s to 60 min. |
| 213 | 10329981 | Contraction resulted in a rapid and transient activation of Raf-1 and MAP kinase kinase 1, a rapid and more sustained activation of MAP kinase and the 90-kDa ribosomal S6 kinase 2, and a dramatic increase in c-fos mRNA expression. |
| 214 | 10329981 | Contraction also resulted in an apparent increase in the association of Raf-1 with p21Ras, although stimulation of MAP kinase signaling occurred independent of Shc, IRS1, and IRS2 tyrosine phosphorylation or the formation of Shc/Grb2 or IRS1/Grb2 complexes. |
| 215 | 10329981 | Insulin was considerably less effective than contraction in stimulating the MAP kinase pathway. |
| 216 | 10329981 | However, insulin, but not contraction, increased p70(S6K) and Akt activities in the muscle. |
| 217 | 10329981 | These results demonstrate that contraction-induced activation of the MAP kinase pathway is independent of proximal steps in insulin and/or growth factor-mediated signaling, and that contraction and insulin have discordant effects with respect to the activation of the MAP kinase pathway vs. p70(S6K) and Akt. |
| 218 | 10329981 | Of the numerous stimulators of MAP kinase in skeletal muscle, contractile activity emerges as a potent and physiologically relevant activator of MAP kinase signaling, and thus activation of this pathway is likely to be an important molecular mechanism by which skeletal muscle cells transduce mechanical and/or biochemical signals into downstream biological responses. |
| 219 | 10329981 | Differential regulation of MAP kinase, p70(S6K), and Akt by contraction and insulin in rat skeletal muscle. |
| 220 | 10329981 | To study the effects of contractile activity on mitogen-activated protein kinase (MAP kinase), p70 S6 kinase (p70(S6K)), and Akt kinase signaling in rat skeletal muscle, hindlimb muscles were contracted by electrical stimulation of the sciatic nerve for periods of 15 s to 60 min. |
| 221 | 10329981 | Contraction resulted in a rapid and transient activation of Raf-1 and MAP kinase kinase 1, a rapid and more sustained activation of MAP kinase and the 90-kDa ribosomal S6 kinase 2, and a dramatic increase in c-fos mRNA expression. |
| 222 | 10329981 | Contraction also resulted in an apparent increase in the association of Raf-1 with p21Ras, although stimulation of MAP kinase signaling occurred independent of Shc, IRS1, and IRS2 tyrosine phosphorylation or the formation of Shc/Grb2 or IRS1/Grb2 complexes. |
| 223 | 10329981 | Insulin was considerably less effective than contraction in stimulating the MAP kinase pathway. |
| 224 | 10329981 | However, insulin, but not contraction, increased p70(S6K) and Akt activities in the muscle. |
| 225 | 10329981 | These results demonstrate that contraction-induced activation of the MAP kinase pathway is independent of proximal steps in insulin and/or growth factor-mediated signaling, and that contraction and insulin have discordant effects with respect to the activation of the MAP kinase pathway vs. p70(S6K) and Akt. |
| 226 | 10329981 | Of the numerous stimulators of MAP kinase in skeletal muscle, contractile activity emerges as a potent and physiologically relevant activator of MAP kinase signaling, and thus activation of this pathway is likely to be an important molecular mechanism by which skeletal muscle cells transduce mechanical and/or biochemical signals into downstream biological responses. |
| 227 | 10329981 | Differential regulation of MAP kinase, p70(S6K), and Akt by contraction and insulin in rat skeletal muscle. |
| 228 | 10329981 | To study the effects of contractile activity on mitogen-activated protein kinase (MAP kinase), p70 S6 kinase (p70(S6K)), and Akt kinase signaling in rat skeletal muscle, hindlimb muscles were contracted by electrical stimulation of the sciatic nerve for periods of 15 s to 60 min. |
| 229 | 10329981 | Contraction resulted in a rapid and transient activation of Raf-1 and MAP kinase kinase 1, a rapid and more sustained activation of MAP kinase and the 90-kDa ribosomal S6 kinase 2, and a dramatic increase in c-fos mRNA expression. |
| 230 | 10329981 | Contraction also resulted in an apparent increase in the association of Raf-1 with p21Ras, although stimulation of MAP kinase signaling occurred independent of Shc, IRS1, and IRS2 tyrosine phosphorylation or the formation of Shc/Grb2 or IRS1/Grb2 complexes. |
| 231 | 10329981 | Insulin was considerably less effective than contraction in stimulating the MAP kinase pathway. |
| 232 | 10329981 | However, insulin, but not contraction, increased p70(S6K) and Akt activities in the muscle. |
| 233 | 10329981 | These results demonstrate that contraction-induced activation of the MAP kinase pathway is independent of proximal steps in insulin and/or growth factor-mediated signaling, and that contraction and insulin have discordant effects with respect to the activation of the MAP kinase pathway vs. p70(S6K) and Akt. |
| 234 | 10329981 | Of the numerous stimulators of MAP kinase in skeletal muscle, contractile activity emerges as a potent and physiologically relevant activator of MAP kinase signaling, and thus activation of this pathway is likely to be an important molecular mechanism by which skeletal muscle cells transduce mechanical and/or biochemical signals into downstream biological responses. |
| 235 | 10329981 | Differential regulation of MAP kinase, p70(S6K), and Akt by contraction and insulin in rat skeletal muscle. |
| 236 | 10329981 | To study the effects of contractile activity on mitogen-activated protein kinase (MAP kinase), p70 S6 kinase (p70(S6K)), and Akt kinase signaling in rat skeletal muscle, hindlimb muscles were contracted by electrical stimulation of the sciatic nerve for periods of 15 s to 60 min. |
| 237 | 10329981 | Contraction resulted in a rapid and transient activation of Raf-1 and MAP kinase kinase 1, a rapid and more sustained activation of MAP kinase and the 90-kDa ribosomal S6 kinase 2, and a dramatic increase in c-fos mRNA expression. |
| 238 | 10329981 | Contraction also resulted in an apparent increase in the association of Raf-1 with p21Ras, although stimulation of MAP kinase signaling occurred independent of Shc, IRS1, and IRS2 tyrosine phosphorylation or the formation of Shc/Grb2 or IRS1/Grb2 complexes. |
| 239 | 10329981 | Insulin was considerably less effective than contraction in stimulating the MAP kinase pathway. |
| 240 | 10329981 | However, insulin, but not contraction, increased p70(S6K) and Akt activities in the muscle. |
| 241 | 10329981 | These results demonstrate that contraction-induced activation of the MAP kinase pathway is independent of proximal steps in insulin and/or growth factor-mediated signaling, and that contraction and insulin have discordant effects with respect to the activation of the MAP kinase pathway vs. p70(S6K) and Akt. |
| 242 | 10329981 | Of the numerous stimulators of MAP kinase in skeletal muscle, contractile activity emerges as a potent and physiologically relevant activator of MAP kinase signaling, and thus activation of this pathway is likely to be an important molecular mechanism by which skeletal muscle cells transduce mechanical and/or biochemical signals into downstream biological responses. |
| 243 | 10594015 | IRS-4 mediates protein kinase B signaling during insulin stimulation without promoting antiapoptosis. |
| 244 | 10594015 | Insulin receptor substrate (IRS) proteins are tyrosine phosphorylated and mediate multiple signals during activation of the receptors for insulin, insulin-like growth factor 1 (IGF-1), and various cytokines. |
| 245 | 10594015 | In order to distinguish common and unique functions of IRS-1, IRS-2, and IRS-4, we expressed them individually in 32D myeloid progenitor cells containing the human insulin receptor (32D(IR)). |
| 246 | 10594015 | Insulin promoted the association of Grb-2 with IRS-1 and IRS-4, whereas IRS-2 weakly bound Grb-2; consequently, IRS-1 and IRS-4 enhanced insulin-stimulated mitogen-activated protein kinase activity. |
| 247 | 10594015 | During insulin stimulation, IRS-1 and IRS-2 strongly bound p85alpha/beta, which activated phosphatidylinositol (PI) 3-kinase, protein kinase B (PKB)/Akt, and p70(s6k), and promoted the phosphorylation of BAD. |
| 248 | 10594015 | IRS-4 also promoted the activation of PKB/Akt and BAD phosphorylation during insulin stimulation; however, it weakly bound or activated p85-associated PI 3-kinase and failed to mediate the activation of p70(s6k). |
| 249 | 10594015 | Insulin strongly inhibited apoptosis of interleukin-3 (IL-3)-deprived 32D(IR) cells expressing IRS-1 or IRS-2 but failed to inhibit apoptosis of cells expressing IRS-4. |
| 250 | 10594015 | Consequently, 32D(IR) cells expressing IRS-4 proliferated slowly during insulin stimulation. |
| 251 | 10594015 | Thus, the activation of PKB/Akt and BAD phosphorylation might not be sufficient to inhibit the apoptosis of IL-3-deprived 32D(IR) cells unless p85-associated PI 3-kinase or p70(s6k) are strongly activated. |
| 252 | 10594015 | IRS-4 mediates protein kinase B signaling during insulin stimulation without promoting antiapoptosis. |
| 253 | 10594015 | Insulin receptor substrate (IRS) proteins are tyrosine phosphorylated and mediate multiple signals during activation of the receptors for insulin, insulin-like growth factor 1 (IGF-1), and various cytokines. |
| 254 | 10594015 | In order to distinguish common and unique functions of IRS-1, IRS-2, and IRS-4, we expressed them individually in 32D myeloid progenitor cells containing the human insulin receptor (32D(IR)). |
| 255 | 10594015 | Insulin promoted the association of Grb-2 with IRS-1 and IRS-4, whereas IRS-2 weakly bound Grb-2; consequently, IRS-1 and IRS-4 enhanced insulin-stimulated mitogen-activated protein kinase activity. |
| 256 | 10594015 | During insulin stimulation, IRS-1 and IRS-2 strongly bound p85alpha/beta, which activated phosphatidylinositol (PI) 3-kinase, protein kinase B (PKB)/Akt, and p70(s6k), and promoted the phosphorylation of BAD. |
| 257 | 10594015 | IRS-4 also promoted the activation of PKB/Akt and BAD phosphorylation during insulin stimulation; however, it weakly bound or activated p85-associated PI 3-kinase and failed to mediate the activation of p70(s6k). |
| 258 | 10594015 | Insulin strongly inhibited apoptosis of interleukin-3 (IL-3)-deprived 32D(IR) cells expressing IRS-1 or IRS-2 but failed to inhibit apoptosis of cells expressing IRS-4. |
| 259 | 10594015 | Consequently, 32D(IR) cells expressing IRS-4 proliferated slowly during insulin stimulation. |
| 260 | 10594015 | Thus, the activation of PKB/Akt and BAD phosphorylation might not be sufficient to inhibit the apoptosis of IL-3-deprived 32D(IR) cells unless p85-associated PI 3-kinase or p70(s6k) are strongly activated. |
| 261 | 10594015 | IRS-4 mediates protein kinase B signaling during insulin stimulation without promoting antiapoptosis. |
| 262 | 10594015 | Insulin receptor substrate (IRS) proteins are tyrosine phosphorylated and mediate multiple signals during activation of the receptors for insulin, insulin-like growth factor 1 (IGF-1), and various cytokines. |
| 263 | 10594015 | In order to distinguish common and unique functions of IRS-1, IRS-2, and IRS-4, we expressed them individually in 32D myeloid progenitor cells containing the human insulin receptor (32D(IR)). |
| 264 | 10594015 | Insulin promoted the association of Grb-2 with IRS-1 and IRS-4, whereas IRS-2 weakly bound Grb-2; consequently, IRS-1 and IRS-4 enhanced insulin-stimulated mitogen-activated protein kinase activity. |
| 265 | 10594015 | During insulin stimulation, IRS-1 and IRS-2 strongly bound p85alpha/beta, which activated phosphatidylinositol (PI) 3-kinase, protein kinase B (PKB)/Akt, and p70(s6k), and promoted the phosphorylation of BAD. |
| 266 | 10594015 | IRS-4 also promoted the activation of PKB/Akt and BAD phosphorylation during insulin stimulation; however, it weakly bound or activated p85-associated PI 3-kinase and failed to mediate the activation of p70(s6k). |
| 267 | 10594015 | Insulin strongly inhibited apoptosis of interleukin-3 (IL-3)-deprived 32D(IR) cells expressing IRS-1 or IRS-2 but failed to inhibit apoptosis of cells expressing IRS-4. |
| 268 | 10594015 | Consequently, 32D(IR) cells expressing IRS-4 proliferated slowly during insulin stimulation. |
| 269 | 10594015 | Thus, the activation of PKB/Akt and BAD phosphorylation might not be sufficient to inhibit the apoptosis of IL-3-deprived 32D(IR) cells unless p85-associated PI 3-kinase or p70(s6k) are strongly activated. |
| 270 | 10706003 | Insulin-stimulated ERK-1 and ERK-2 activity was markedly increased in STZ-diabetic rats. |
| 271 | 10706003 | Chronic BMOV treatment normalized the activity of ERK-2 in the diabetic treated animals, whereas the activity of ERK-1 was unaffected. |
| 272 | 10706003 | In contrast to ERK-1 and ERK-2, the activity of the ribosomal S6 kinase p90rsk was decreased in STZ-diabetic rats. |
| 273 | 10706003 | Basal p70 S6K activity was increased about 2.5-fold in the untreated diabetic group and no further increase in activity was observed after insulin stimulation. |
| 274 | 10706003 | BMOV treatment did not correct the changes in p70 S6K activity in either the basal or insulin-stimulated states. |
| 275 | 10706003 | In conclusion (i) the activity of ERK-1, ERK-2 and p90rsk were altered in skeletal muscle of STZ-diabetic rats; (ii) the glucoregulatory effects of BMOV were accompanied by concurrent improvement in the activities of ERK-2 and p90rsk; and (iii) there appears to be a dissociation between the activation of ERK-2 and p90rsk, suggesting that the regulation of p90rsk may be much more complex in vivo. |
| 276 | 10706003 | Insulin-stimulated ERK-1 and ERK-2 activity was markedly increased in STZ-diabetic rats. |
| 277 | 10706003 | Chronic BMOV treatment normalized the activity of ERK-2 in the diabetic treated animals, whereas the activity of ERK-1 was unaffected. |
| 278 | 10706003 | In contrast to ERK-1 and ERK-2, the activity of the ribosomal S6 kinase p90rsk was decreased in STZ-diabetic rats. |
| 279 | 10706003 | Basal p70 S6K activity was increased about 2.5-fold in the untreated diabetic group and no further increase in activity was observed after insulin stimulation. |
| 280 | 10706003 | BMOV treatment did not correct the changes in p70 S6K activity in either the basal or insulin-stimulated states. |
| 281 | 10706003 | In conclusion (i) the activity of ERK-1, ERK-2 and p90rsk were altered in skeletal muscle of STZ-diabetic rats; (ii) the glucoregulatory effects of BMOV were accompanied by concurrent improvement in the activities of ERK-2 and p90rsk; and (iii) there appears to be a dissociation between the activation of ERK-2 and p90rsk, suggesting that the regulation of p90rsk may be much more complex in vivo. |
| 282 | 10958681 | Cellular compartmentalization in insulin action: altered signaling by a lipid-modified IRS-1. |
| 283 | 10958681 | To determine the importance of this distribution to IRS-1-mediated signaling, we constructed a prenylated, constitutively membrane-bound IRS-1 by adding the COOH-terminal 9 amino acids from p21(ras), including the CAAX motif, to IRS-1 (IRS-CAAX) and analyzed its function in 32D cells expressing the insulin receptor. |
| 284 | 10958681 | Insulin-stimulated tyrosyl phosphorylation of IRS-CAAX was slightly decreased, while IRS-CAAX-mediated phosphatidylinositol 3'-kinase (PI3'-kinase) binding and activation were decreased by approximately 75% compared to those for wild-type IRS-1. |
| 285 | 10958681 | Similarly, expression of IRS-CAAX desensitized insulin-stimulated [(3)H]thymidine incorporation into DNA by about an order of magnitude compared to IRS-1. |
| 286 | 10958681 | By contrast, IRS-CAAX-expressing cells demonstrated increased signaling by mitogen-activated protein kinase, Akt, and p70(S6) kinase in response to insulin. |
| 287 | 10958681 | Hence, tight association with the membrane increased IRS-1 serine phosphorylation and reduced coupling between the insulin receptor, PI3'-kinase, and proliferative signaling while enhancing other signaling pathways. |
| 288 | 10958681 | Thus, the correct distribution of IRS-1 between the cytoplasm and membrane compartments is critical to the normal balance in the network of insulin signaling. |
| 289 | 11027274 | The gene for the p85alpha regulatory subunit yields three splicing variants, p85alpha, AS53/p55alpha, and p50alpha. |
| 290 | 11027274 | To determine if these regulatory subunits differ in their effects on enzyme activity and signal transduction from insulin receptor substrate (IRS) proteins under physiological conditions, we expressed each regulatory subunit in fully differentiated L6 myotubes using adenovirus-mediated gene transfer with or without coexpression of the p110alpha catalytic subunit. |
| 291 | 11027274 | Insulin stimulation of two kinases downstream from PI-3 kinase, Akt and p70 S6 kinase (p70(S6K)), was decreased in cells expressing p85alpha or AS53 but not in cells expressing p50alpha. |
| 292 | 11027274 | Similar inhibition of PI 3-kinase, Akt, and p70(S6K) was observed, even when p110alpha was coexpressed with p85alpha or AS53. |
| 293 | 11027274 | The gene for the p85alpha regulatory subunit yields three splicing variants, p85alpha, AS53/p55alpha, and p50alpha. |
| 294 | 11027274 | To determine if these regulatory subunits differ in their effects on enzyme activity and signal transduction from insulin receptor substrate (IRS) proteins under physiological conditions, we expressed each regulatory subunit in fully differentiated L6 myotubes using adenovirus-mediated gene transfer with or without coexpression of the p110alpha catalytic subunit. |
| 295 | 11027274 | Insulin stimulation of two kinases downstream from PI-3 kinase, Akt and p70 S6 kinase (p70(S6K)), was decreased in cells expressing p85alpha or AS53 but not in cells expressing p50alpha. |
| 296 | 11027274 | Similar inhibition of PI 3-kinase, Akt, and p70(S6K) was observed, even when p110alpha was coexpressed with p85alpha or AS53. |
| 297 | 11272147 | Recent findings have demonstrated that the branched-chain amino acid leucine can activate the translational regulators, phosphorylated heat- and acid-stable protein regulated by insulin (PHAS-I) and p70 S6 kinase (p70S6k), in an insulin-independent and rapamycin-sensitive manner through mammalian target of rapamycin (mTOR), although the mechanism for this activation is undefined. |
| 298 | 11272147 | It has been previously established that leucine-induced insulin secretion by beta-cells involves increased mitochondrial metabolism by oxidative decarboxylation and allosteric activation of glutamate dehydrogenase (GDH). |
| 299 | 11549666 | Insulin stimulation of glycogen synthase activity as well as phosphorylation of MAPK, p70 S6 kinase, and protein kinase B (Akt) were blocked by the phosphatidylinositol 3-kinase inhibitors wortmannin (50 nM) and LY294002 (10 microM). |
| 300 | 11549666 | This increased sensitivity of diabetic muscle to impairment of insulin-stimulated glycogen synthase activity occurs together with diminished insulin-stimulation (by 40%) of IRS-1-associated phosphatidylinositol 3-kinase activity in the same cells. |
| 301 | 11549666 | Protein expression of IRS-1, p85, p110, Akt, p70 S6 kinase, and MAPK were normal in diabetic cells, as was insulin-stimulated phosphorylation of Akt, p70 S6 kinase, and MAPK. |
| 302 | 11549666 | These studies indicate that, despite prolonged growth and differentiation of diabetic muscle under normal metabolic culture conditions, defects of insulin-stimulated phosphatidylinositol 3-kinase and glycogen synthase activity in diabetic muscle persist, consistent with intrinsic (rather than acquired) defects of insulin action. |
| 303 | 11549666 | Insulin stimulation of glycogen synthase activity as well as phosphorylation of MAPK, p70 S6 kinase, and protein kinase B (Akt) were blocked by the phosphatidylinositol 3-kinase inhibitors wortmannin (50 nM) and LY294002 (10 microM). |
| 304 | 11549666 | This increased sensitivity of diabetic muscle to impairment of insulin-stimulated glycogen synthase activity occurs together with diminished insulin-stimulation (by 40%) of IRS-1-associated phosphatidylinositol 3-kinase activity in the same cells. |
| 305 | 11549666 | Protein expression of IRS-1, p85, p110, Akt, p70 S6 kinase, and MAPK were normal in diabetic cells, as was insulin-stimulated phosphorylation of Akt, p70 S6 kinase, and MAPK. |
| 306 | 11549666 | These studies indicate that, despite prolonged growth and differentiation of diabetic muscle under normal metabolic culture conditions, defects of insulin-stimulated phosphatidylinositol 3-kinase and glycogen synthase activity in diabetic muscle persist, consistent with intrinsic (rather than acquired) defects of insulin action. |
| 307 | 11574405 | Pancreatic duodenal homeobox-1 (PDX-1) is a homeodomain protein that plays an important role in the development of the pancreas and in maintaining the identity and function of the islets of Langerhans. |
| 308 | 11574405 | Glucose and insulin regulate PDX-1 by way of a signaling pathway involving phosphatidylinositol 3-kinase (PI 3-kinase) and SAPK2/p38. |
| 309 | 11574405 | Insulin and sodium arsenite, an activator of the stress-activated pathway, also stimulated PDX-1 movement from the nuclear periphery to the nucleoplasm. |
| 310 | 11574405 | Glucose- and insulin-stimulated translocation of PDX-1 to the nucleoplasm was inhibited by wortmannin and SB 203580, indicating that a pathway involving PI 3-kinase and SAPK2/p38 was involved; translocation was unaffected by PD 098959 and rapamycin, suggesting that neither mitogen-activated protein kinase nor p70(s6k) were involved. |
| 311 | 11574405 | These results demonstrated that PDX-1 shuttles between the nuclear periphery and nucleoplasm in response to changes in glucose and insulin concentrations and that these events are dependent on PI 3-kinase, SAPK2/p38, and a nuclear phosphatase(s). |
| 312 | 11695998 | The regulation by insulin of the expression of the p85alpha regulatory subunit of phosphoinositide 3-kinase (PI 3-kinase) is impaired in skeletal muscle and adipose tissue of type 2 diabetic patients. |
| 313 | 11695998 | In muscle, p85alpha and p50alpha mRNAs were the most abundant, and p55alpha represented less than 20% of all grb-1-derived mRNAs. |
| 314 | 11695998 | In adipose tissue, p85alpha was expressed predominantly and p55alpha mRNA was not detectable. |
| 315 | 11695998 | In diabetic patients, the effect of insulin on p85alpha and p50alpha mRNAs was blunted, and largely reduced on p55alpha transcripts. |
| 316 | 11695998 | In cultured human myotubes, up-regulation of p85alpha, p55alpha and p50alpha mRNAs by insulin was abolished by LY294002 (10 microM) and by rapamycin (50 nM), suggesting that the PI 3-kinase/protein kinase B/p70 S6 kinase pathway could be involved in the stimulation of grb-1 gene expression by insulin in human muscle cells. |
| 317 | 11782951 | Regulation of cell size in growth, development and human disease: PI3K, PKB and S6K. |
| 318 | 11782951 | Here we focus on two components of this pathway, PKB and S6K, and briefly review the experiments that initially uncovered their roles in cell size control. |
| 319 | 11782951 | Finally, we have utilized two contemporary studies involving PKB- and S6K-deficient mice as a paradigm to underscore the importance of cell size and to accurately delineate the connections between signaling pathways for human disease, such as diabetes mellitus. |
| 320 | 11782951 | Regulation of cell size in growth, development and human disease: PI3K, PKB and S6K. |
| 321 | 11782951 | Here we focus on two components of this pathway, PKB and S6K, and briefly review the experiments that initially uncovered their roles in cell size control. |
| 322 | 11782951 | Finally, we have utilized two contemporary studies involving PKB- and S6K-deficient mice as a paradigm to underscore the importance of cell size and to accurately delineate the connections between signaling pathways for human disease, such as diabetes mellitus. |
| 323 | 11782951 | Regulation of cell size in growth, development and human disease: PI3K, PKB and S6K. |
| 324 | 11782951 | Here we focus on two components of this pathway, PKB and S6K, and briefly review the experiments that initially uncovered their roles in cell size control. |
| 325 | 11782951 | Finally, we have utilized two contemporary studies involving PKB- and S6K-deficient mice as a paradigm to underscore the importance of cell size and to accurately delineate the connections between signaling pathways for human disease, such as diabetes mellitus. |
| 326 | 11826398 | Insulin signaling in the transcriptional and posttranscriptional regulation of CYP2E1 expression. |
| 327 | 11826398 | Diabetes has been reported to increase the expression of cytochrome P450 (CYP) 2E1 messenger RNA (mRNA) and protein several-fold, and enhanced expression has been associated with elevated ketone bodies. |
| 328 | 11826398 | Primary cultured rat hepatocytes were used to explore ketone body and insulin regulation of CYP2E1 expression. |
| 329 | 11826398 | Insulin produced a concentration-dependent decrease in CYP2E1 mRNA levels, and insulin receptor immunoprecipitation showed a correspondence between receptor phosphorylation and the decrease in CYP2E1 mRNA levels at physiologic levels of insulin. |
| 330 | 11826398 | The phosphatidylinositol 3-kinase (PI3-kinase) inhibitors wortmannin or LY294002 and rapamycin, an inhibitor of p70 S6 kinase phosphorylation, ameliorated the insulin-mediated decrease in CYP2E1 mRNA levels. |
| 331 | 11826398 | Geldanamycin, which inhibits Src kinase, also abrogated the insulin-mediated decrease in CYP2E1 mRNA levels. |
| 332 | 11826398 | In contrast, the protein kinase C (PKC) inhibitor bisindolylmaleimide, the mitogen-activated protein kinase kinase (MEK) inhibitor PD98059, and the p38 mitogen-activated protein (MAP) kinase inhibitor SB202190 did not affect the insulin-mediated decrease in CYP2E1. |
| 333 | 11826398 | CYP2E1 mRNA half-life decreased from approximately 48 hours in the absence of insulin to approximately 15 hours at 10 nmol/L insulin, and this decrease was prevented by wortmannin. |
| 334 | 11826398 | The half-life of CYP2B mRNA was increased by insulin, whereas that of CYP3A was unaffected. |
| 335 | 11826398 | Analysis of CYP2E1 gene transcription using heterogeneous nuclear RNA (hnRNA) showed that insulin suppressed CYP2E1 transcription. |
| 336 | 11826398 | In conclusion, these data show involvement of transcriptional and posttranscriptional mechanisms in the insulin-mediated regulation of CYP2E1 and implicate PI3-kinase, p70 S6 kinase, and Src kinase in mediating these effects. |
| 337 | 11826398 | Insulin signaling in the transcriptional and posttranscriptional regulation of CYP2E1 expression. |
| 338 | 11826398 | Diabetes has been reported to increase the expression of cytochrome P450 (CYP) 2E1 messenger RNA (mRNA) and protein several-fold, and enhanced expression has been associated with elevated ketone bodies. |
| 339 | 11826398 | Primary cultured rat hepatocytes were used to explore ketone body and insulin regulation of CYP2E1 expression. |
| 340 | 11826398 | Insulin produced a concentration-dependent decrease in CYP2E1 mRNA levels, and insulin receptor immunoprecipitation showed a correspondence between receptor phosphorylation and the decrease in CYP2E1 mRNA levels at physiologic levels of insulin. |
| 341 | 11826398 | The phosphatidylinositol 3-kinase (PI3-kinase) inhibitors wortmannin or LY294002 and rapamycin, an inhibitor of p70 S6 kinase phosphorylation, ameliorated the insulin-mediated decrease in CYP2E1 mRNA levels. |
| 342 | 11826398 | Geldanamycin, which inhibits Src kinase, also abrogated the insulin-mediated decrease in CYP2E1 mRNA levels. |
| 343 | 11826398 | In contrast, the protein kinase C (PKC) inhibitor bisindolylmaleimide, the mitogen-activated protein kinase kinase (MEK) inhibitor PD98059, and the p38 mitogen-activated protein (MAP) kinase inhibitor SB202190 did not affect the insulin-mediated decrease in CYP2E1. |
| 344 | 11826398 | CYP2E1 mRNA half-life decreased from approximately 48 hours in the absence of insulin to approximately 15 hours at 10 nmol/L insulin, and this decrease was prevented by wortmannin. |
| 345 | 11826398 | The half-life of CYP2B mRNA was increased by insulin, whereas that of CYP3A was unaffected. |
| 346 | 11826398 | Analysis of CYP2E1 gene transcription using heterogeneous nuclear RNA (hnRNA) showed that insulin suppressed CYP2E1 transcription. |
| 347 | 11826398 | In conclusion, these data show involvement of transcriptional and posttranscriptional mechanisms in the insulin-mediated regulation of CYP2E1 and implicate PI3-kinase, p70 S6 kinase, and Src kinase in mediating these effects. |
| 348 | 11916909 | Orally administered leucine enhances protein synthesis in skeletal muscle of diabetic rats in the absence of increases in 4E-BP1 or S6K1 phosphorylation. |
| 349 | 11916909 | Consequently, association of the mRNA cap-binding protein eukaryotic initiation factor (eIF)4E with 4E-BP1 was reduced to 50% of control values, and eIF4G*eIF4E complex assembly was increased 80%. |
| 350 | 11916909 | Furthermore, leucine increased the phosphorylation of the 70-kDa ribosomal protein S6 (rp S6) and the ribosomal protein S6 kinase (S6K1). |
| 351 | 11916909 | Nonetheless, in diabetic rats, leucine increased protein synthesis by 53% without concomitant changes in the phosphorylation of 4E-BP1 or S6K1. |
| 352 | 11916909 | Phosphorylation of 4E-BP1 and S6K1 was increased in diabetic rats infused with insulin in a dose-dependent manner, and the response was enhanced by leucine. |
| 353 | 11916909 | The insulin-dependent mechanism is associated with increased phosphorylation of 4E-BP1 and S6K1. |
| 354 | 11916909 | Orally administered leucine enhances protein synthesis in skeletal muscle of diabetic rats in the absence of increases in 4E-BP1 or S6K1 phosphorylation. |
| 355 | 11916909 | Consequently, association of the mRNA cap-binding protein eukaryotic initiation factor (eIF)4E with 4E-BP1 was reduced to 50% of control values, and eIF4G*eIF4E complex assembly was increased 80%. |
| 356 | 11916909 | Furthermore, leucine increased the phosphorylation of the 70-kDa ribosomal protein S6 (rp S6) and the ribosomal protein S6 kinase (S6K1). |
| 357 | 11916909 | Nonetheless, in diabetic rats, leucine increased protein synthesis by 53% without concomitant changes in the phosphorylation of 4E-BP1 or S6K1. |
| 358 | 11916909 | Phosphorylation of 4E-BP1 and S6K1 was increased in diabetic rats infused with insulin in a dose-dependent manner, and the response was enhanced by leucine. |
| 359 | 11916909 | The insulin-dependent mechanism is associated with increased phosphorylation of 4E-BP1 and S6K1. |
| 360 | 11916909 | Orally administered leucine enhances protein synthesis in skeletal muscle of diabetic rats in the absence of increases in 4E-BP1 or S6K1 phosphorylation. |
| 361 | 11916909 | Consequently, association of the mRNA cap-binding protein eukaryotic initiation factor (eIF)4E with 4E-BP1 was reduced to 50% of control values, and eIF4G*eIF4E complex assembly was increased 80%. |
| 362 | 11916909 | Furthermore, leucine increased the phosphorylation of the 70-kDa ribosomal protein S6 (rp S6) and the ribosomal protein S6 kinase (S6K1). |
| 363 | 11916909 | Nonetheless, in diabetic rats, leucine increased protein synthesis by 53% without concomitant changes in the phosphorylation of 4E-BP1 or S6K1. |
| 364 | 11916909 | Phosphorylation of 4E-BP1 and S6K1 was increased in diabetic rats infused with insulin in a dose-dependent manner, and the response was enhanced by leucine. |
| 365 | 11916909 | The insulin-dependent mechanism is associated with increased phosphorylation of 4E-BP1 and S6K1. |
| 366 | 11916909 | Orally administered leucine enhances protein synthesis in skeletal muscle of diabetic rats in the absence of increases in 4E-BP1 or S6K1 phosphorylation. |
| 367 | 11916909 | Consequently, association of the mRNA cap-binding protein eukaryotic initiation factor (eIF)4E with 4E-BP1 was reduced to 50% of control values, and eIF4G*eIF4E complex assembly was increased 80%. |
| 368 | 11916909 | Furthermore, leucine increased the phosphorylation of the 70-kDa ribosomal protein S6 (rp S6) and the ribosomal protein S6 kinase (S6K1). |
| 369 | 11916909 | Nonetheless, in diabetic rats, leucine increased protein synthesis by 53% without concomitant changes in the phosphorylation of 4E-BP1 or S6K1. |
| 370 | 11916909 | Phosphorylation of 4E-BP1 and S6K1 was increased in diabetic rats infused with insulin in a dose-dependent manner, and the response was enhanced by leucine. |
| 371 | 11916909 | The insulin-dependent mechanism is associated with increased phosphorylation of 4E-BP1 and S6K1. |
| 372 | 11916909 | Orally administered leucine enhances protein synthesis in skeletal muscle of diabetic rats in the absence of increases in 4E-BP1 or S6K1 phosphorylation. |
| 373 | 11916909 | Consequently, association of the mRNA cap-binding protein eukaryotic initiation factor (eIF)4E with 4E-BP1 was reduced to 50% of control values, and eIF4G*eIF4E complex assembly was increased 80%. |
| 374 | 11916909 | Furthermore, leucine increased the phosphorylation of the 70-kDa ribosomal protein S6 (rp S6) and the ribosomal protein S6 kinase (S6K1). |
| 375 | 11916909 | Nonetheless, in diabetic rats, leucine increased protein synthesis by 53% without concomitant changes in the phosphorylation of 4E-BP1 or S6K1. |
| 376 | 11916909 | Phosphorylation of 4E-BP1 and S6K1 was increased in diabetic rats infused with insulin in a dose-dependent manner, and the response was enhanced by leucine. |
| 377 | 11916909 | The insulin-dependent mechanism is associated with increased phosphorylation of 4E-BP1 and S6K1. |
| 378 | 11916914 | Activation of IRS-2-mediated signal transduction by IGF-1, but not TGF-alpha or EGF, augments pancreatic beta-cell proliferation. |
| 379 | 11916914 | Transforming growth factor (TGF)-alpha- and epidermal growth factor (EGF)-induced signal transduction was directly compared with that of glucose and insulin-like growth factor-1 (IGF-1) in INS-1 cells. |
| 380 | 11916914 | TGF-alpha/EGF transiently (<20 min) induced phosphorylation of extracellular-regulated kinase (Erk)-1/2 (>20-fold), glycogen synthase kinase (GSK)-3 (>10-fold), and protein kinase B (PKB) (Ser(473) and Thr(308)), but did not increase [(3)H]thymidine incorporation. |
| 381 | 11916914 | In contrast, phosphorylation of Erk1/2, GSK-3, and PKB in response to glucose and IGF-1 was more prolonged (>24 h) and, though not as robust as TGF-alpha/EGF, did increase beta-cell proliferation. |
| 382 | 11916914 | Phosphorylation of p70(S6K) was also increased by IGF-1/glucose, but not by TGF-alpha/EGF, despite upstream PKB activation. |
| 383 | 11916914 | It was found that IGF-1 induced phosphatidylinositol 3-kinase (PI3K) association with insulin receptor substrate (IRS)-1 and -2 in a glucose-dependent manner, whereas TGF-alpha/EGF did not. |
| 384 | 11916914 | The importance of specific IRS-2-mediated signaling events was emphasized in that adenoviral-mediated overexpression of IRS-2 further increased glucose/IGF-1-induced beta-cell proliferation (more than twofold; P < 0.05) compared with control or adenoviral-mediated IRS-1 overexpressing INS-1 cells. |
| 385 | 11916914 | Neither IRS-1 nor IRS-2 overexpression induced a beta-cell proliferative response to TGF-alpha/EGF. |
| 386 | 11916914 | Thus, a prolonged activation of Erk1/2 and PI3K signaling pathways is important in committing a beta-cell to a mitogenic event, and it is likely that this sustained activation is instigated by signal transduction occurring specifically through IRS-2. |
| 387 | 11978789 | Glucagon-like peptide-2 receptor activation engages bad and glycogen synthase kinase-3 in a protein kinase A-dependent manner and prevents apoptosis following inhibition of phosphatidylinositol 3-kinase. |
| 388 | 11978789 | We now demonstrate that GLP-2, in a cycloheximide-insensitive manner, enhanced survival in baby hamster kidney cells stably transfected with the rat GLP-2R; reduced mitochondrial cytochrome c efflux; and attenuated the caspase-dependent cleavage of Akt, poly(ADP-ribose) polymerase, and beta-catenin following inhibition of phosphatidylinositol 3-kinase (PI3K) by LY294002. |
| 389 | 11978789 | The prosurvival effects of GLP-2 on LY294002-induced cell death were independent of Akt, p90(Rsk), or p70 S6 kinase activation; were mimicked by forskolin; and were abrogated by inhibition of protein kinase A (PKA) activity. |
| 390 | 11978789 | GLP-2 inhibited activation of glycogen synthase kinase-3 (GSK-3) through phosphorylation at Ser(21) in GSK-3alpha and at Ser(9) in GSK-3beta in a PI3K-independent, PKA-dependent manner. |
| 391 | 11978789 | GLP-2 reduced LY294002-induced mitochondrial association of endogenous Bad and Bax and stimulated phosphorylation of a transfected Bad fusion protein at Ser(155) in a PI3K-independent, but H89-sensitive manner, a modification known to suppress Bad pro-apoptotic activity. |
| 392 | 11978789 | These results suggest that GLP-2R signaling enhances cell survival independently of PI3K/Akt by inhibiting the activity of a subset of pro-apoptotic downstream targets of Akt in a PKA-dependent manner. |
| 393 | 12026190 | Oral administration of leucine stimulates phosphorylation of 4E-bP1 and S6K 1 in skeletal muscle but not in liver of diabetic rats. |
| 394 | 12026190 | Leucine performs a signaling role to enhance protein synthesis by phosphorylating eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) and 70-kDa ribosomal protein S6 kinase (S6K1), two key regulatory proteins involved in the initiation of mRNA translation. |
| 395 | 12026190 | The purpose of the current study was to assess whether the phosphorylation of 4E-BP1 and S6K1 was increased in skeletal muscle and liver by an oral administration of leucine to diabetic rats and to determine the in vivo contribution of insulin to a leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation. |
| 396 | 12026190 | Leucine administration resulted in enhanced phosphorylation of 4E-BP1 and S6K1 in skeletal muscle and in liver of nondiabetic rats. |
| 397 | 12026190 | The stimulatory action of leucine on the phosphorylation of 4E-BP1 and S6K1 in skeletal muscle was not abolished in rats with streptozotocin-induced diabetes. |
| 398 | 12026190 | In contrast, leucine administration did not stimulate the phosphorylation of 4E-BP1 and S6K1 in the liver of diabetic rats. |
| 399 | 12026190 | These findings suggest that in skeletal muscle, leucine functions as a nutritional signaling molecule that independently regulates the phosphorylation states of 4E-BP1 and S6K1. |
| 400 | 12026190 | In contrast to skeletal muscle, insulin is essential in mediating the leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation in liver. leucine, 4E-BP1, S6K1, translation initiation, diabetes |
| 401 | 12026190 | Oral administration of leucine stimulates phosphorylation of 4E-bP1 and S6K 1 in skeletal muscle but not in liver of diabetic rats. |
| 402 | 12026190 | Leucine performs a signaling role to enhance protein synthesis by phosphorylating eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) and 70-kDa ribosomal protein S6 kinase (S6K1), two key regulatory proteins involved in the initiation of mRNA translation. |
| 403 | 12026190 | The purpose of the current study was to assess whether the phosphorylation of 4E-BP1 and S6K1 was increased in skeletal muscle and liver by an oral administration of leucine to diabetic rats and to determine the in vivo contribution of insulin to a leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation. |
| 404 | 12026190 | Leucine administration resulted in enhanced phosphorylation of 4E-BP1 and S6K1 in skeletal muscle and in liver of nondiabetic rats. |
| 405 | 12026190 | The stimulatory action of leucine on the phosphorylation of 4E-BP1 and S6K1 in skeletal muscle was not abolished in rats with streptozotocin-induced diabetes. |
| 406 | 12026190 | In contrast, leucine administration did not stimulate the phosphorylation of 4E-BP1 and S6K1 in the liver of diabetic rats. |
| 407 | 12026190 | These findings suggest that in skeletal muscle, leucine functions as a nutritional signaling molecule that independently regulates the phosphorylation states of 4E-BP1 and S6K1. |
| 408 | 12026190 | In contrast to skeletal muscle, insulin is essential in mediating the leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation in liver. leucine, 4E-BP1, S6K1, translation initiation, diabetes |
| 409 | 12026190 | Oral administration of leucine stimulates phosphorylation of 4E-bP1 and S6K 1 in skeletal muscle but not in liver of diabetic rats. |
| 410 | 12026190 | Leucine performs a signaling role to enhance protein synthesis by phosphorylating eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) and 70-kDa ribosomal protein S6 kinase (S6K1), two key regulatory proteins involved in the initiation of mRNA translation. |
| 411 | 12026190 | The purpose of the current study was to assess whether the phosphorylation of 4E-BP1 and S6K1 was increased in skeletal muscle and liver by an oral administration of leucine to diabetic rats and to determine the in vivo contribution of insulin to a leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation. |
| 412 | 12026190 | Leucine administration resulted in enhanced phosphorylation of 4E-BP1 and S6K1 in skeletal muscle and in liver of nondiabetic rats. |
| 413 | 12026190 | The stimulatory action of leucine on the phosphorylation of 4E-BP1 and S6K1 in skeletal muscle was not abolished in rats with streptozotocin-induced diabetes. |
| 414 | 12026190 | In contrast, leucine administration did not stimulate the phosphorylation of 4E-BP1 and S6K1 in the liver of diabetic rats. |
| 415 | 12026190 | These findings suggest that in skeletal muscle, leucine functions as a nutritional signaling molecule that independently regulates the phosphorylation states of 4E-BP1 and S6K1. |
| 416 | 12026190 | In contrast to skeletal muscle, insulin is essential in mediating the leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation in liver. leucine, 4E-BP1, S6K1, translation initiation, diabetes |
| 417 | 12026190 | Oral administration of leucine stimulates phosphorylation of 4E-bP1 and S6K 1 in skeletal muscle but not in liver of diabetic rats. |
| 418 | 12026190 | Leucine performs a signaling role to enhance protein synthesis by phosphorylating eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) and 70-kDa ribosomal protein S6 kinase (S6K1), two key regulatory proteins involved in the initiation of mRNA translation. |
| 419 | 12026190 | The purpose of the current study was to assess whether the phosphorylation of 4E-BP1 and S6K1 was increased in skeletal muscle and liver by an oral administration of leucine to diabetic rats and to determine the in vivo contribution of insulin to a leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation. |
| 420 | 12026190 | Leucine administration resulted in enhanced phosphorylation of 4E-BP1 and S6K1 in skeletal muscle and in liver of nondiabetic rats. |
| 421 | 12026190 | The stimulatory action of leucine on the phosphorylation of 4E-BP1 and S6K1 in skeletal muscle was not abolished in rats with streptozotocin-induced diabetes. |
| 422 | 12026190 | In contrast, leucine administration did not stimulate the phosphorylation of 4E-BP1 and S6K1 in the liver of diabetic rats. |
| 423 | 12026190 | These findings suggest that in skeletal muscle, leucine functions as a nutritional signaling molecule that independently regulates the phosphorylation states of 4E-BP1 and S6K1. |
| 424 | 12026190 | In contrast to skeletal muscle, insulin is essential in mediating the leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation in liver. leucine, 4E-BP1, S6K1, translation initiation, diabetes |
| 425 | 12026190 | Oral administration of leucine stimulates phosphorylation of 4E-bP1 and S6K 1 in skeletal muscle but not in liver of diabetic rats. |
| 426 | 12026190 | Leucine performs a signaling role to enhance protein synthesis by phosphorylating eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) and 70-kDa ribosomal protein S6 kinase (S6K1), two key regulatory proteins involved in the initiation of mRNA translation. |
| 427 | 12026190 | The purpose of the current study was to assess whether the phosphorylation of 4E-BP1 and S6K1 was increased in skeletal muscle and liver by an oral administration of leucine to diabetic rats and to determine the in vivo contribution of insulin to a leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation. |
| 428 | 12026190 | Leucine administration resulted in enhanced phosphorylation of 4E-BP1 and S6K1 in skeletal muscle and in liver of nondiabetic rats. |
| 429 | 12026190 | The stimulatory action of leucine on the phosphorylation of 4E-BP1 and S6K1 in skeletal muscle was not abolished in rats with streptozotocin-induced diabetes. |
| 430 | 12026190 | In contrast, leucine administration did not stimulate the phosphorylation of 4E-BP1 and S6K1 in the liver of diabetic rats. |
| 431 | 12026190 | These findings suggest that in skeletal muscle, leucine functions as a nutritional signaling molecule that independently regulates the phosphorylation states of 4E-BP1 and S6K1. |
| 432 | 12026190 | In contrast to skeletal muscle, insulin is essential in mediating the leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation in liver. leucine, 4E-BP1, S6K1, translation initiation, diabetes |
| 433 | 12026190 | Oral administration of leucine stimulates phosphorylation of 4E-bP1 and S6K 1 in skeletal muscle but not in liver of diabetic rats. |
| 434 | 12026190 | Leucine performs a signaling role to enhance protein synthesis by phosphorylating eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) and 70-kDa ribosomal protein S6 kinase (S6K1), two key regulatory proteins involved in the initiation of mRNA translation. |
| 435 | 12026190 | The purpose of the current study was to assess whether the phosphorylation of 4E-BP1 and S6K1 was increased in skeletal muscle and liver by an oral administration of leucine to diabetic rats and to determine the in vivo contribution of insulin to a leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation. |
| 436 | 12026190 | Leucine administration resulted in enhanced phosphorylation of 4E-BP1 and S6K1 in skeletal muscle and in liver of nondiabetic rats. |
| 437 | 12026190 | The stimulatory action of leucine on the phosphorylation of 4E-BP1 and S6K1 in skeletal muscle was not abolished in rats with streptozotocin-induced diabetes. |
| 438 | 12026190 | In contrast, leucine administration did not stimulate the phosphorylation of 4E-BP1 and S6K1 in the liver of diabetic rats. |
| 439 | 12026190 | These findings suggest that in skeletal muscle, leucine functions as a nutritional signaling molecule that independently regulates the phosphorylation states of 4E-BP1 and S6K1. |
| 440 | 12026190 | In contrast to skeletal muscle, insulin is essential in mediating the leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation in liver. leucine, 4E-BP1, S6K1, translation initiation, diabetes |
| 441 | 12026190 | Oral administration of leucine stimulates phosphorylation of 4E-bP1 and S6K 1 in skeletal muscle but not in liver of diabetic rats. |
| 442 | 12026190 | Leucine performs a signaling role to enhance protein synthesis by phosphorylating eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) and 70-kDa ribosomal protein S6 kinase (S6K1), two key regulatory proteins involved in the initiation of mRNA translation. |
| 443 | 12026190 | The purpose of the current study was to assess whether the phosphorylation of 4E-BP1 and S6K1 was increased in skeletal muscle and liver by an oral administration of leucine to diabetic rats and to determine the in vivo contribution of insulin to a leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation. |
| 444 | 12026190 | Leucine administration resulted in enhanced phosphorylation of 4E-BP1 and S6K1 in skeletal muscle and in liver of nondiabetic rats. |
| 445 | 12026190 | The stimulatory action of leucine on the phosphorylation of 4E-BP1 and S6K1 in skeletal muscle was not abolished in rats with streptozotocin-induced diabetes. |
| 446 | 12026190 | In contrast, leucine administration did not stimulate the phosphorylation of 4E-BP1 and S6K1 in the liver of diabetic rats. |
| 447 | 12026190 | These findings suggest that in skeletal muscle, leucine functions as a nutritional signaling molecule that independently regulates the phosphorylation states of 4E-BP1 and S6K1. |
| 448 | 12026190 | In contrast to skeletal muscle, insulin is essential in mediating the leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation in liver. leucine, 4E-BP1, S6K1, translation initiation, diabetes |
| 449 | 12026190 | Oral administration of leucine stimulates phosphorylation of 4E-bP1 and S6K 1 in skeletal muscle but not in liver of diabetic rats. |
| 450 | 12026190 | Leucine performs a signaling role to enhance protein synthesis by phosphorylating eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) and 70-kDa ribosomal protein S6 kinase (S6K1), two key regulatory proteins involved in the initiation of mRNA translation. |
| 451 | 12026190 | The purpose of the current study was to assess whether the phosphorylation of 4E-BP1 and S6K1 was increased in skeletal muscle and liver by an oral administration of leucine to diabetic rats and to determine the in vivo contribution of insulin to a leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation. |
| 452 | 12026190 | Leucine administration resulted in enhanced phosphorylation of 4E-BP1 and S6K1 in skeletal muscle and in liver of nondiabetic rats. |
| 453 | 12026190 | The stimulatory action of leucine on the phosphorylation of 4E-BP1 and S6K1 in skeletal muscle was not abolished in rats with streptozotocin-induced diabetes. |
| 454 | 12026190 | In contrast, leucine administration did not stimulate the phosphorylation of 4E-BP1 and S6K1 in the liver of diabetic rats. |
| 455 | 12026190 | These findings suggest that in skeletal muscle, leucine functions as a nutritional signaling molecule that independently regulates the phosphorylation states of 4E-BP1 and S6K1. |
| 456 | 12026190 | In contrast to skeletal muscle, insulin is essential in mediating the leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation in liver. leucine, 4E-BP1, S6K1, translation initiation, diabetes |
| 457 | 12070227 | It is now well established that physical exercise or muscle contractile activity can activate three of the mitogen-activated protein kinase signaling pathways, including the extracellular signal-regulated kinase 1 and 2, the c-Jun NH(2)-terminal kinase, and the p38. |
| 458 | 12070227 | Exercise can also robustly increase activity of the AMP-activated protein kinase, as well as several additional molecules, including glycogen synthase kinase 3, Akt, and the p70 S6 kinase. |
| 459 | 12118006 | EGCG also mimics insulin by increasing phosphoinositide 3-kinase, mitogen-activated protein kinase, and p70(s6k) activity. |
| 460 | 12351422 | Mammalian target of rapamycin (mTOR) is a serine and threonine protein kinase that regulates numerous cellular functions, in particular, the initiation of protein translation. mTOR-mediated phosphorylation of both the translational repressor eukaryotic initiation factor 4E binding protein-1 and p70 S6 kinase are early events that control the translation initiation process. |
| 461 | 12415748 | The discussion will focus on the role of the ribosomal protein S6 kinase (S6K) signaling pathway in the regulation of cell growth and proliferation. |
| 462 | 12415748 | Loss of dS6K function in Drosophila melanogaster demonstrated its paramount importance in development and growth control (Montagne et al., 1999), whereas deletion of the S6K1 gene in the mouse led to an animal of reduced size and the identification of the S6K1 homologue, S6K2 (Shima et al., 1998). |
| 463 | 12415748 | The discussion will focus on the role of the ribosomal protein S6 kinase (S6K) signaling pathway in the regulation of cell growth and proliferation. |
| 464 | 12415748 | Loss of dS6K function in Drosophila melanogaster demonstrated its paramount importance in development and growth control (Montagne et al., 1999), whereas deletion of the S6K1 gene in the mouse led to an animal of reduced size and the identification of the S6K1 homologue, S6K2 (Shima et al., 1998). |
| 465 | 12502492 | Differential regulation of lipogenesis and leptin production by independent signaling pathways and rosiglitazone during human adipocyte differentiation. |
| 466 | 12502492 | We used inhibitors of p70(S6) kinase, p42/44 mitogen-activated protein kinase (MAPK), p38 MAPK, and phosphatidylinositol 3-kinase (PI3K). |
| 467 | 12502492 | Human preadipocytes were induced to differentiate in insulin, dexamethasone, triiodothyronine, and 3-isobutyl-1-methylxanthine in the presence or absence of inhibitors and the peroxisome proliferator-activated receptor (PPAR)-gamma activator rosiglitazone. |
| 468 | 12502492 | None of the inhibitors significantly inhibited protein content over 20 days, but lipid content and lipogenic activity were inhibited by p70(S6) kinase and p38 MAPK inhibition but not by p42/44 MAPK or PI3K inhibition. |
| 469 | 12502492 | We conclude that PI3K and p42/44 MAPK pathways are not critical to the differentiation program leading to lipid accumulation, but stimulation of leptin secretion is dependent on these as well as the p70(S6) kinase and p38 MAPK signaling pathways. |
| 470 | 12502492 | Differential regulation of lipogenesis and leptin production by independent signaling pathways and rosiglitazone during human adipocyte differentiation. |
| 471 | 12502492 | We used inhibitors of p70(S6) kinase, p42/44 mitogen-activated protein kinase (MAPK), p38 MAPK, and phosphatidylinositol 3-kinase (PI3K). |
| 472 | 12502492 | Human preadipocytes were induced to differentiate in insulin, dexamethasone, triiodothyronine, and 3-isobutyl-1-methylxanthine in the presence or absence of inhibitors and the peroxisome proliferator-activated receptor (PPAR)-gamma activator rosiglitazone. |
| 473 | 12502492 | None of the inhibitors significantly inhibited protein content over 20 days, but lipid content and lipogenic activity were inhibited by p70(S6) kinase and p38 MAPK inhibition but not by p42/44 MAPK or PI3K inhibition. |
| 474 | 12502492 | We conclude that PI3K and p42/44 MAPK pathways are not critical to the differentiation program leading to lipid accumulation, but stimulation of leptin secretion is dependent on these as well as the p70(S6) kinase and p38 MAPK signaling pathways. |
| 475 | 12502492 | Differential regulation of lipogenesis and leptin production by independent signaling pathways and rosiglitazone during human adipocyte differentiation. |
| 476 | 12502492 | We used inhibitors of p70(S6) kinase, p42/44 mitogen-activated protein kinase (MAPK), p38 MAPK, and phosphatidylinositol 3-kinase (PI3K). |
| 477 | 12502492 | Human preadipocytes were induced to differentiate in insulin, dexamethasone, triiodothyronine, and 3-isobutyl-1-methylxanthine in the presence or absence of inhibitors and the peroxisome proliferator-activated receptor (PPAR)-gamma activator rosiglitazone. |
| 478 | 12502492 | None of the inhibitors significantly inhibited protein content over 20 days, but lipid content and lipogenic activity were inhibited by p70(S6) kinase and p38 MAPK inhibition but not by p42/44 MAPK or PI3K inhibition. |
| 479 | 12502492 | We conclude that PI3K and p42/44 MAPK pathways are not critical to the differentiation program leading to lipid accumulation, but stimulation of leptin secretion is dependent on these as well as the p70(S6) kinase and p38 MAPK signaling pathways. |
| 480 | 12663469 | Differential activation mechanisms of Erk-1/2 and p70(S6K) by glucose in pancreatic beta-cells. |
| 481 | 12663469 | Glucose can activate the mitogen-activated kinases, Erk-1/2, and the ribosomal-S6 kinase, p70(S6K), in beta-cells, contributing to an increase in mitogenesis. |
| 482 | 12663469 | However, the signaling mechanism by which glucose induces Erk-1/2 and p70(S6K) phosphorylation activation is undefined. |
| 483 | 12663469 | Increased glucose metabolism increases [Ca(2+)](i) and [cAMP], and it was investigated if these secondary signals were linked to glucose-induced Erk-1/2 and p70(S6K) activation in pancreatic beta-cells. |
| 484 | 12663469 | Blocking Ca(2+) influx with verapamil, or inhibiting protein kinase A (PKA) with H89, prevented glucose-induced Erk-1/2 phosphorylation. |
| 485 | 12663469 | Collectively, our study indicates that a glucose-induced rise in [Ca(2+)](i) leads to cAMP-induced activation of PKA that acts downstream of Ras and upstream of the MAP/Erk kinase, MEK, to mediate Erk-1/2 phosphorylation via phosphorylation activation of Raf-1. |
| 486 | 12663469 | In contrast, glucose-induced p70(S6K) activation, in the same beta-cells, was mediated by a distinct signaling pathway independent of Ca(2+)/cAMP, most likely via mTOR-kinase acting as an "ATP-sensor." |
| 487 | 12663469 | Differential activation mechanisms of Erk-1/2 and p70(S6K) by glucose in pancreatic beta-cells. |
| 488 | 12663469 | Glucose can activate the mitogen-activated kinases, Erk-1/2, and the ribosomal-S6 kinase, p70(S6K), in beta-cells, contributing to an increase in mitogenesis. |
| 489 | 12663469 | However, the signaling mechanism by which glucose induces Erk-1/2 and p70(S6K) phosphorylation activation is undefined. |
| 490 | 12663469 | Increased glucose metabolism increases [Ca(2+)](i) and [cAMP], and it was investigated if these secondary signals were linked to glucose-induced Erk-1/2 and p70(S6K) activation in pancreatic beta-cells. |
| 491 | 12663469 | Blocking Ca(2+) influx with verapamil, or inhibiting protein kinase A (PKA) with H89, prevented glucose-induced Erk-1/2 phosphorylation. |
| 492 | 12663469 | Collectively, our study indicates that a glucose-induced rise in [Ca(2+)](i) leads to cAMP-induced activation of PKA that acts downstream of Ras and upstream of the MAP/Erk kinase, MEK, to mediate Erk-1/2 phosphorylation via phosphorylation activation of Raf-1. |
| 493 | 12663469 | In contrast, glucose-induced p70(S6K) activation, in the same beta-cells, was mediated by a distinct signaling pathway independent of Ca(2+)/cAMP, most likely via mTOR-kinase acting as an "ATP-sensor." |
| 494 | 12663469 | Differential activation mechanisms of Erk-1/2 and p70(S6K) by glucose in pancreatic beta-cells. |
| 495 | 12663469 | Glucose can activate the mitogen-activated kinases, Erk-1/2, and the ribosomal-S6 kinase, p70(S6K), in beta-cells, contributing to an increase in mitogenesis. |
| 496 | 12663469 | However, the signaling mechanism by which glucose induces Erk-1/2 and p70(S6K) phosphorylation activation is undefined. |
| 497 | 12663469 | Increased glucose metabolism increases [Ca(2+)](i) and [cAMP], and it was investigated if these secondary signals were linked to glucose-induced Erk-1/2 and p70(S6K) activation in pancreatic beta-cells. |
| 498 | 12663469 | Blocking Ca(2+) influx with verapamil, or inhibiting protein kinase A (PKA) with H89, prevented glucose-induced Erk-1/2 phosphorylation. |
| 499 | 12663469 | Collectively, our study indicates that a glucose-induced rise in [Ca(2+)](i) leads to cAMP-induced activation of PKA that acts downstream of Ras and upstream of the MAP/Erk kinase, MEK, to mediate Erk-1/2 phosphorylation via phosphorylation activation of Raf-1. |
| 500 | 12663469 | In contrast, glucose-induced p70(S6K) activation, in the same beta-cells, was mediated by a distinct signaling pathway independent of Ca(2+)/cAMP, most likely via mTOR-kinase acting as an "ATP-sensor." |
| 501 | 12663469 | Differential activation mechanisms of Erk-1/2 and p70(S6K) by glucose in pancreatic beta-cells. |
| 502 | 12663469 | Glucose can activate the mitogen-activated kinases, Erk-1/2, and the ribosomal-S6 kinase, p70(S6K), in beta-cells, contributing to an increase in mitogenesis. |
| 503 | 12663469 | However, the signaling mechanism by which glucose induces Erk-1/2 and p70(S6K) phosphorylation activation is undefined. |
| 504 | 12663469 | Increased glucose metabolism increases [Ca(2+)](i) and [cAMP], and it was investigated if these secondary signals were linked to glucose-induced Erk-1/2 and p70(S6K) activation in pancreatic beta-cells. |
| 505 | 12663469 | Blocking Ca(2+) influx with verapamil, or inhibiting protein kinase A (PKA) with H89, prevented glucose-induced Erk-1/2 phosphorylation. |
| 506 | 12663469 | Collectively, our study indicates that a glucose-induced rise in [Ca(2+)](i) leads to cAMP-induced activation of PKA that acts downstream of Ras and upstream of the MAP/Erk kinase, MEK, to mediate Erk-1/2 phosphorylation via phosphorylation activation of Raf-1. |
| 507 | 12663469 | In contrast, glucose-induced p70(S6K) activation, in the same beta-cells, was mediated by a distinct signaling pathway independent of Ca(2+)/cAMP, most likely via mTOR-kinase acting as an "ATP-sensor." |
| 508 | 12663469 | Differential activation mechanisms of Erk-1/2 and p70(S6K) by glucose in pancreatic beta-cells. |
| 509 | 12663469 | Glucose can activate the mitogen-activated kinases, Erk-1/2, and the ribosomal-S6 kinase, p70(S6K), in beta-cells, contributing to an increase in mitogenesis. |
| 510 | 12663469 | However, the signaling mechanism by which glucose induces Erk-1/2 and p70(S6K) phosphorylation activation is undefined. |
| 511 | 12663469 | Increased glucose metabolism increases [Ca(2+)](i) and [cAMP], and it was investigated if these secondary signals were linked to glucose-induced Erk-1/2 and p70(S6K) activation in pancreatic beta-cells. |
| 512 | 12663469 | Blocking Ca(2+) influx with verapamil, or inhibiting protein kinase A (PKA) with H89, prevented glucose-induced Erk-1/2 phosphorylation. |
| 513 | 12663469 | Collectively, our study indicates that a glucose-induced rise in [Ca(2+)](i) leads to cAMP-induced activation of PKA that acts downstream of Ras and upstream of the MAP/Erk kinase, MEK, to mediate Erk-1/2 phosphorylation via phosphorylation activation of Raf-1. |
| 514 | 12663469 | In contrast, glucose-induced p70(S6K) activation, in the same beta-cells, was mediated by a distinct signaling pathway independent of Ca(2+)/cAMP, most likely via mTOR-kinase acting as an "ATP-sensor." |
| 515 | 12855688 | Requirement for 3-phosphoinositide-kependent dinase-1 (PDK-1) in insulin-induced glucose uptake in immortalized brown adipocytes. |
| 516 | 12855688 | To provide insight into the physiological importance of 3-phosphoinositide-dependent kinase-1 (PDK-1) in the metabolic actions of insulin, we have generated mice that harbor a PDK-1 gene containing LoxP sites (PDK-1(lox/lox) mice) and established immortalized brown preadipocyte cell lines both from these animals and from wild-type mice. |
| 517 | 12855688 | In Cre-expressing PDK-1(lox/lox) adipocytes in which the abundance of PDK-1 was reduced by approximately 85%, the insulin-induced phosphorylation both of Akt on threonine 308 and of p70 S6 kinase on threonine-389 was markedly inhibited. |
| 518 | 12855688 | The phosphorylation both of Akt on serine 473 and of p42 and p44 isoforms of mitogen-activated protein kinase induced by insulin was not affected by Cre expression, indicating that the latter specifically inhibits PDK-1-dependent signaling. |
| 519 | 12855688 | Both glucose uptake and the translocation of glucose transporter 4 to the plasma membrane induced by insulin as well as glucose uptake induced by a constitutively active form of phosphoinositide 3-kinase were also greatly inhibited by Cre expression in PDK-1(lox/lox) adipocytes. |
| 520 | 12855688 | Phosphorylation of AMP-activated protein kinase and glucose uptake induced by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) were not affected by Cre expression in PDK-1(lox/lox) adipocytes. |
| 521 | 12855688 | These results indicate that PDK-1 is essential for insulin-induced glucose uptake in adipocytes. |
| 522 | 14555183 | Phosphatidylinositol 3-kinase in angiotensin II-induced hypertrophy of vascular smooth muscle cells. |
| 523 | 14555183 | Angiotensin II time and dose dependently stimulated phosphorylation of 4E-BP1 through the angiotensin AT(1) receptor. |
| 524 | 14555183 | Pretreatment with wortmannin or 2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), a PI 3-kinase inhibitor, suppressed angiotensin II-induced phosphorylation, but a mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) kinase-1 (MEK-1) inhibitor, 2'-Amino-3'-methoxyflavone (PD98059), and a p38 MAPK inhibitor, 4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), had no effect. |
| 525 | 14555183 | With regard to the involvement of mammalian target of rapamycin (mTOR) and p70 S6 kinase, angiotensin II-induced phosphorylation was abolished by pretreatment with rapamycin, but not by tosylphenylalanine chloromethyl ketone or tosyllysine chloromethyl ketone. |
| 526 | 14555183 | Thus, angiotensin II induces the phosphorylation of 4E-BP1 via the PI 3-kinase/mTOR pathway, but not via ERK or p70 S6 kinase. |
| 527 | 14555183 | Phosphatidylinositol 3-kinase in angiotensin II-induced hypertrophy of vascular smooth muscle cells. |
| 528 | 14555183 | Angiotensin II time and dose dependently stimulated phosphorylation of 4E-BP1 through the angiotensin AT(1) receptor. |
| 529 | 14555183 | Pretreatment with wortmannin or 2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), a PI 3-kinase inhibitor, suppressed angiotensin II-induced phosphorylation, but a mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) kinase-1 (MEK-1) inhibitor, 2'-Amino-3'-methoxyflavone (PD98059), and a p38 MAPK inhibitor, 4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), had no effect. |
| 530 | 14555183 | With regard to the involvement of mammalian target of rapamycin (mTOR) and p70 S6 kinase, angiotensin II-induced phosphorylation was abolished by pretreatment with rapamycin, but not by tosylphenylalanine chloromethyl ketone or tosyllysine chloromethyl ketone. |
| 531 | 14555183 | Thus, angiotensin II induces the phosphorylation of 4E-BP1 via the PI 3-kinase/mTOR pathway, but not via ERK or p70 S6 kinase. |
| 532 | 14560955 | The p70 S6 kinase (p70 S6K) was the first signaling element in mammalian cells shown to be inhibited by rapamycin. |
| 533 | 14560955 | The activity of the p70 S6K in mammalian cell is upregulated by extracellular amino acids (especially leucine) and by signals from receptor tyrosine kinases (RTKs), primarily through activation of the type 1A PI-3 kinase. |
| 534 | 14560955 | The amino acid-/rapamycin-sensitive input and the PI-3 kinase input are co-dominant but largely independent, in that deletion of the amino-terminal and carboxy-terminal noncatalytic sequences flanking the p70 S6K catalytic domain renders the kinase insensitive to inhibition by both rapamycin and by withdrawal of amino acids, whereas this p70 S6K mutant remains responsive to activation by RTKs and to inhibition by wortmannin. |
| 535 | 14560955 | At a molecular level, this dual control of p70 S6K activity is attributable to phosphorylation of the two p70 S6K sites: The Ptd Ins 3,4,5P3-dependent kinasel (PDK1) phosphorylates p70 S6K at a Thr on the activation loop, whereas mTOR phosphorylates a Thr located in a hydrophobic motif carboxyterminal to the catalytic domain. |
| 536 | 14560955 | Together these two phosphorylations engender a strong, positively cooperative activation of p70 S6K, so that each is indispensable for physiologic regulation. |
| 537 | 14560955 | Like RTKs, the p70 S6K appears early in metazoan evolution and comes to represent an important site at which the more ancient, nutrient-responsive TOR pathway converges with the RTK/PI-3 kinase pathway in the control of cell growth. |
| 538 | 14560955 | Dual regulation of p70 S6K is seen in Drosophila; however, this convergence is not yet evident in Caenorhabditis elegans, wherein nutrient activation of the insulin receptor (InsR) pathway negatively regulates dauer development and longevity, whereas the TOR pathway regulates overall mRNA translation through effectors distinct from p70 S6K, as in yeast. |
| 539 | 14560955 | The C. elegans TOR and InsR pathways show none of the cross- or convergent regulation seen in mammalian cells. |
| 540 | 14560955 | The p70 S6 kinase (p70 S6K) was the first signaling element in mammalian cells shown to be inhibited by rapamycin. |
| 541 | 14560955 | The activity of the p70 S6K in mammalian cell is upregulated by extracellular amino acids (especially leucine) and by signals from receptor tyrosine kinases (RTKs), primarily through activation of the type 1A PI-3 kinase. |
| 542 | 14560955 | The amino acid-/rapamycin-sensitive input and the PI-3 kinase input are co-dominant but largely independent, in that deletion of the amino-terminal and carboxy-terminal noncatalytic sequences flanking the p70 S6K catalytic domain renders the kinase insensitive to inhibition by both rapamycin and by withdrawal of amino acids, whereas this p70 S6K mutant remains responsive to activation by RTKs and to inhibition by wortmannin. |
| 543 | 14560955 | At a molecular level, this dual control of p70 S6K activity is attributable to phosphorylation of the two p70 S6K sites: The Ptd Ins 3,4,5P3-dependent kinasel (PDK1) phosphorylates p70 S6K at a Thr on the activation loop, whereas mTOR phosphorylates a Thr located in a hydrophobic motif carboxyterminal to the catalytic domain. |
| 544 | 14560955 | Together these two phosphorylations engender a strong, positively cooperative activation of p70 S6K, so that each is indispensable for physiologic regulation. |
| 545 | 14560955 | Like RTKs, the p70 S6K appears early in metazoan evolution and comes to represent an important site at which the more ancient, nutrient-responsive TOR pathway converges with the RTK/PI-3 kinase pathway in the control of cell growth. |
| 546 | 14560955 | Dual regulation of p70 S6K is seen in Drosophila; however, this convergence is not yet evident in Caenorhabditis elegans, wherein nutrient activation of the insulin receptor (InsR) pathway negatively regulates dauer development and longevity, whereas the TOR pathway regulates overall mRNA translation through effectors distinct from p70 S6K, as in yeast. |
| 547 | 14560955 | The C. elegans TOR and InsR pathways show none of the cross- or convergent regulation seen in mammalian cells. |
| 548 | 14560955 | The p70 S6 kinase (p70 S6K) was the first signaling element in mammalian cells shown to be inhibited by rapamycin. |
| 549 | 14560955 | The activity of the p70 S6K in mammalian cell is upregulated by extracellular amino acids (especially leucine) and by signals from receptor tyrosine kinases (RTKs), primarily through activation of the type 1A PI-3 kinase. |
| 550 | 14560955 | The amino acid-/rapamycin-sensitive input and the PI-3 kinase input are co-dominant but largely independent, in that deletion of the amino-terminal and carboxy-terminal noncatalytic sequences flanking the p70 S6K catalytic domain renders the kinase insensitive to inhibition by both rapamycin and by withdrawal of amino acids, whereas this p70 S6K mutant remains responsive to activation by RTKs and to inhibition by wortmannin. |
| 551 | 14560955 | At a molecular level, this dual control of p70 S6K activity is attributable to phosphorylation of the two p70 S6K sites: The Ptd Ins 3,4,5P3-dependent kinasel (PDK1) phosphorylates p70 S6K at a Thr on the activation loop, whereas mTOR phosphorylates a Thr located in a hydrophobic motif carboxyterminal to the catalytic domain. |
| 552 | 14560955 | Together these two phosphorylations engender a strong, positively cooperative activation of p70 S6K, so that each is indispensable for physiologic regulation. |
| 553 | 14560955 | Like RTKs, the p70 S6K appears early in metazoan evolution and comes to represent an important site at which the more ancient, nutrient-responsive TOR pathway converges with the RTK/PI-3 kinase pathway in the control of cell growth. |
| 554 | 14560955 | Dual regulation of p70 S6K is seen in Drosophila; however, this convergence is not yet evident in Caenorhabditis elegans, wherein nutrient activation of the insulin receptor (InsR) pathway negatively regulates dauer development and longevity, whereas the TOR pathway regulates overall mRNA translation through effectors distinct from p70 S6K, as in yeast. |
| 555 | 14560955 | The C. elegans TOR and InsR pathways show none of the cross- or convergent regulation seen in mammalian cells. |
| 556 | 14560955 | The p70 S6 kinase (p70 S6K) was the first signaling element in mammalian cells shown to be inhibited by rapamycin. |
| 557 | 14560955 | The activity of the p70 S6K in mammalian cell is upregulated by extracellular amino acids (especially leucine) and by signals from receptor tyrosine kinases (RTKs), primarily through activation of the type 1A PI-3 kinase. |
| 558 | 14560955 | The amino acid-/rapamycin-sensitive input and the PI-3 kinase input are co-dominant but largely independent, in that deletion of the amino-terminal and carboxy-terminal noncatalytic sequences flanking the p70 S6K catalytic domain renders the kinase insensitive to inhibition by both rapamycin and by withdrawal of amino acids, whereas this p70 S6K mutant remains responsive to activation by RTKs and to inhibition by wortmannin. |
| 559 | 14560955 | At a molecular level, this dual control of p70 S6K activity is attributable to phosphorylation of the two p70 S6K sites: The Ptd Ins 3,4,5P3-dependent kinasel (PDK1) phosphorylates p70 S6K at a Thr on the activation loop, whereas mTOR phosphorylates a Thr located in a hydrophobic motif carboxyterminal to the catalytic domain. |
| 560 | 14560955 | Together these two phosphorylations engender a strong, positively cooperative activation of p70 S6K, so that each is indispensable for physiologic regulation. |
| 561 | 14560955 | Like RTKs, the p70 S6K appears early in metazoan evolution and comes to represent an important site at which the more ancient, nutrient-responsive TOR pathway converges with the RTK/PI-3 kinase pathway in the control of cell growth. |
| 562 | 14560955 | Dual regulation of p70 S6K is seen in Drosophila; however, this convergence is not yet evident in Caenorhabditis elegans, wherein nutrient activation of the insulin receptor (InsR) pathway negatively regulates dauer development and longevity, whereas the TOR pathway regulates overall mRNA translation through effectors distinct from p70 S6K, as in yeast. |
| 563 | 14560955 | The C. elegans TOR and InsR pathways show none of the cross- or convergent regulation seen in mammalian cells. |
| 564 | 14560955 | The p70 S6 kinase (p70 S6K) was the first signaling element in mammalian cells shown to be inhibited by rapamycin. |
| 565 | 14560955 | The activity of the p70 S6K in mammalian cell is upregulated by extracellular amino acids (especially leucine) and by signals from receptor tyrosine kinases (RTKs), primarily through activation of the type 1A PI-3 kinase. |
| 566 | 14560955 | The amino acid-/rapamycin-sensitive input and the PI-3 kinase input are co-dominant but largely independent, in that deletion of the amino-terminal and carboxy-terminal noncatalytic sequences flanking the p70 S6K catalytic domain renders the kinase insensitive to inhibition by both rapamycin and by withdrawal of amino acids, whereas this p70 S6K mutant remains responsive to activation by RTKs and to inhibition by wortmannin. |
| 567 | 14560955 | At a molecular level, this dual control of p70 S6K activity is attributable to phosphorylation of the two p70 S6K sites: The Ptd Ins 3,4,5P3-dependent kinasel (PDK1) phosphorylates p70 S6K at a Thr on the activation loop, whereas mTOR phosphorylates a Thr located in a hydrophobic motif carboxyterminal to the catalytic domain. |
| 568 | 14560955 | Together these two phosphorylations engender a strong, positively cooperative activation of p70 S6K, so that each is indispensable for physiologic regulation. |
| 569 | 14560955 | Like RTKs, the p70 S6K appears early in metazoan evolution and comes to represent an important site at which the more ancient, nutrient-responsive TOR pathway converges with the RTK/PI-3 kinase pathway in the control of cell growth. |
| 570 | 14560955 | Dual regulation of p70 S6K is seen in Drosophila; however, this convergence is not yet evident in Caenorhabditis elegans, wherein nutrient activation of the insulin receptor (InsR) pathway negatively regulates dauer development and longevity, whereas the TOR pathway regulates overall mRNA translation through effectors distinct from p70 S6K, as in yeast. |
| 571 | 14560955 | The C. elegans TOR and InsR pathways show none of the cross- or convergent regulation seen in mammalian cells. |
| 572 | 14560955 | The p70 S6 kinase (p70 S6K) was the first signaling element in mammalian cells shown to be inhibited by rapamycin. |
| 573 | 14560955 | The activity of the p70 S6K in mammalian cell is upregulated by extracellular amino acids (especially leucine) and by signals from receptor tyrosine kinases (RTKs), primarily through activation of the type 1A PI-3 kinase. |
| 574 | 14560955 | The amino acid-/rapamycin-sensitive input and the PI-3 kinase input are co-dominant but largely independent, in that deletion of the amino-terminal and carboxy-terminal noncatalytic sequences flanking the p70 S6K catalytic domain renders the kinase insensitive to inhibition by both rapamycin and by withdrawal of amino acids, whereas this p70 S6K mutant remains responsive to activation by RTKs and to inhibition by wortmannin. |
| 575 | 14560955 | At a molecular level, this dual control of p70 S6K activity is attributable to phosphorylation of the two p70 S6K sites: The Ptd Ins 3,4,5P3-dependent kinasel (PDK1) phosphorylates p70 S6K at a Thr on the activation loop, whereas mTOR phosphorylates a Thr located in a hydrophobic motif carboxyterminal to the catalytic domain. |
| 576 | 14560955 | Together these two phosphorylations engender a strong, positively cooperative activation of p70 S6K, so that each is indispensable for physiologic regulation. |
| 577 | 14560955 | Like RTKs, the p70 S6K appears early in metazoan evolution and comes to represent an important site at which the more ancient, nutrient-responsive TOR pathway converges with the RTK/PI-3 kinase pathway in the control of cell growth. |
| 578 | 14560955 | Dual regulation of p70 S6K is seen in Drosophila; however, this convergence is not yet evident in Caenorhabditis elegans, wherein nutrient activation of the insulin receptor (InsR) pathway negatively regulates dauer development and longevity, whereas the TOR pathway regulates overall mRNA translation through effectors distinct from p70 S6K, as in yeast. |
| 579 | 14560955 | The C. elegans TOR and InsR pathways show none of the cross- or convergent regulation seen in mammalian cells. |
| 580 | 14560955 | The p70 S6 kinase (p70 S6K) was the first signaling element in mammalian cells shown to be inhibited by rapamycin. |
| 581 | 14560955 | The activity of the p70 S6K in mammalian cell is upregulated by extracellular amino acids (especially leucine) and by signals from receptor tyrosine kinases (RTKs), primarily through activation of the type 1A PI-3 kinase. |
| 582 | 14560955 | The amino acid-/rapamycin-sensitive input and the PI-3 kinase input are co-dominant but largely independent, in that deletion of the amino-terminal and carboxy-terminal noncatalytic sequences flanking the p70 S6K catalytic domain renders the kinase insensitive to inhibition by both rapamycin and by withdrawal of amino acids, whereas this p70 S6K mutant remains responsive to activation by RTKs and to inhibition by wortmannin. |
| 583 | 14560955 | At a molecular level, this dual control of p70 S6K activity is attributable to phosphorylation of the two p70 S6K sites: The Ptd Ins 3,4,5P3-dependent kinasel (PDK1) phosphorylates p70 S6K at a Thr on the activation loop, whereas mTOR phosphorylates a Thr located in a hydrophobic motif carboxyterminal to the catalytic domain. |
| 584 | 14560955 | Together these two phosphorylations engender a strong, positively cooperative activation of p70 S6K, so that each is indispensable for physiologic regulation. |
| 585 | 14560955 | Like RTKs, the p70 S6K appears early in metazoan evolution and comes to represent an important site at which the more ancient, nutrient-responsive TOR pathway converges with the RTK/PI-3 kinase pathway in the control of cell growth. |
| 586 | 14560955 | Dual regulation of p70 S6K is seen in Drosophila; however, this convergence is not yet evident in Caenorhabditis elegans, wherein nutrient activation of the insulin receptor (InsR) pathway negatively regulates dauer development and longevity, whereas the TOR pathway regulates overall mRNA translation through effectors distinct from p70 S6K, as in yeast. |
| 587 | 14560955 | The C. elegans TOR and InsR pathways show none of the cross- or convergent regulation seen in mammalian cells. |
| 588 | 14623899 | Nutrient-dependent and insulin-stimulated phosphorylation of insulin receptor substrate-1 on serine 302 correlates with increased insulin signaling. |
| 589 | 14623899 | Ser/Thr phosphorylation of insulin receptor substrate IRS-1 regulates insulin signaling, but the relevant phosphorylated residues and their potential functions during insulin-stimulated signal transduction are difficult to resolve. |
| 590 | 14623899 | We used a sequence-specific polyclonal antibody directed against phosphorylated Ser(302) to study IRS-1-mediated signaling during insulin and insulin-like growth factor IGF-I stimulation. |
| 591 | 14623899 | Insulin or IGF-I stimulated phosphorylation of Ser(302) in various cell backgrounds and in murine muscle. |
| 592 | 14623899 | The NH(2)-terminal c-Jun kinase did not phosphorylate Ser(302). |
| 593 | 14623899 | Replacing Ser(302) with alanine significantly reduced insulin-stimulated tyrosine phosphorylation of IRS-1 and p85 binding and reduced insulin-stimulated phosphorylation of p70(S6K), ribosomal S6 protein, and 4E-BP1; however, this mutation had no effect on insulin-stimulated Akt or glycogen synthase kinase 3beta phosphorylation. |
| 594 | 14623899 | Replacing Ser(302) with alanine reduced insulin/IGF-I-stimulated DNA synthesis. |
| 595 | 14623899 | We conclude that Ser(302) phosphorylation integrates nutrient availability with insulin/IGF-I signaling to promote mitogenesis and cell growth. |
| 596 | 15533996 | Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. |
| 597 | 15653324 | The lipid kinase phosphoinositide 3-kinase (PI3K) is activated in response to various extracellular signals including peptide growth factors such as insulin and insulin-like growth factors (IGFs). |
| 598 | 15653324 | Phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P(3)] generated by PI3K is central to the diverse responses elicited by insulin, including glucose homeostasis, proliferation, survival and cell growth. |
| 599 | 15653324 | The actions of lipid phosphatases have been considered to be the main means of attenuating PI3K signalling, whereby the principal 3-phosphatase - phosphatase and tensin homologue deleted on chromosome 10 (PTEN) - dephosphorylates PtdIns(3,4,5)P(3), reversing the action of PI3K. |
| 600 | 15653324 | This finding, together with earlier work, strongly suggests that a major form of negative feedback inhibition of PI3K results from activated growth signalling via mammalian target of rapamycin (mTOR) and the p70 S6 kinase (S6K) - a pathway that could have consequences for the development of type 2 diabetes and tuberous sclerosis complex. |
| 601 | 16183639 | Brief glutamatergic stimulation of neurons from fetal mice, cultured in vitro for 6 days, activates the mTOR-S6 kinase, ERK1/2 and Akt pathways, to an extent approaching that elicited by brain-derived neurotrophic factor. |
| 602 | 16183639 | In contrast, sustained glutamatergic stimulation inhibits ERK, Akt, and S6K. |
| 603 | 16183639 | Added singly, dopamine gives slight, and norepinephrine a more significant, activation of ERK and S6K; both catecholeamines, however, enhance glutamatergic activation of S6K but not ERK. |
| 604 | 16183639 | Elongation factor 2 (EF2) is phosphorylated and inhibited by the eEF2 kinase (CaM kinase III); the latter is inhibited by the S6K or Rsk. |
| 605 | 16183639 | Brief glutamatergic stimulation of neurons from fetal mice, cultured in vitro for 6 days, activates the mTOR-S6 kinase, ERK1/2 and Akt pathways, to an extent approaching that elicited by brain-derived neurotrophic factor. |
| 606 | 16183639 | In contrast, sustained glutamatergic stimulation inhibits ERK, Akt, and S6K. |
| 607 | 16183639 | Added singly, dopamine gives slight, and norepinephrine a more significant, activation of ERK and S6K; both catecholeamines, however, enhance glutamatergic activation of S6K but not ERK. |
| 608 | 16183639 | Elongation factor 2 (EF2) is phosphorylated and inhibited by the eEF2 kinase (CaM kinase III); the latter is inhibited by the S6K or Rsk. |
| 609 | 16183639 | Brief glutamatergic stimulation of neurons from fetal mice, cultured in vitro for 6 days, activates the mTOR-S6 kinase, ERK1/2 and Akt pathways, to an extent approaching that elicited by brain-derived neurotrophic factor. |
| 610 | 16183639 | In contrast, sustained glutamatergic stimulation inhibits ERK, Akt, and S6K. |
| 611 | 16183639 | Added singly, dopamine gives slight, and norepinephrine a more significant, activation of ERK and S6K; both catecholeamines, however, enhance glutamatergic activation of S6K but not ERK. |
| 612 | 16183639 | Elongation factor 2 (EF2) is phosphorylated and inhibited by the eEF2 kinase (CaM kinase III); the latter is inhibited by the S6K or Rsk. |
| 613 | 16186396 | Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation. |
| 614 | 16186396 | Excessive tumor necrosis factor-alpha (TNF-alpha) concentrations have been implicated in the development of insulin resistance, but direct evidence in humans is lacking. |
| 615 | 16186396 | Here, we demonstrate that TNF-alpha infusion in healthy humans induces insulin resistance in skeletal muscle, without effect on endogenous glucose production, as estimated by a combined euglycemic insulin clamp and stable isotope tracer method. |
| 616 | 16186396 | TNF-alpha directly impairs glucose uptake and metabolism by altering insulin signal transduction. |
| 617 | 16186396 | TNF-alpha infusion increases phosphorylation of p70 S6 kinase, extracellular signal-regulated kinase-1/2, and c-Jun NH(2)-terminal kinase, concomitant with increased serine and reduced tyrosine phosphorylation of insulin receptor substrate-1. |
| 618 | 16186396 | These signaling effects are associated with impaired phosphorylation of Akt substrate 160, the most proximal step identified in the canonical insulin signaling cascade regulating GLUT4 translocation and glucose uptake. |
| 619 | 16186396 | Thus, excessive concentrations of TNF-alpha negatively regulate insulin signaling and whole-body glucose uptake in humans. |
| 620 | 16293713 | Identification of the insulin signaling cascade in the regulation of alpha-class glutathione S-transferase expression in primary cultured rat hepatocytes. |
| 621 | 16293713 | We reported previously that insulin elevated alpha-class glutathione S-transferase (GSTs) protein levels in primary cultured rat hepatocytes (Kim et al., 2003b). |
| 622 | 16293713 | In contrast, glucagon down-regulated alpha- and pi-class GST expression, and mechanistic research implicated cAMP and protein kinase A in this process (Kim et al., 2003b). |
| 623 | 16293713 | The present study examines the signaling pathways involved in the regulation of alpha-class GST in response to insulin in primary cultured rat hepatocytes. |
| 624 | 16293713 | Protein levels of GSTA1/2 and GSTA3/5 and activity of GST toward 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole (NBD) were increased in an insulin concentration-dependent manner. |
| 625 | 16293713 | Treatment of cells with the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] or rapamycin, an inhibitor of mammalian target of rapamycin and ribosomal p70 S6 kinase (p70S6K) phosphorylation, or with an adenovirus containing green fluorescent protein and a dominant-negative and kinase-dead Akt, effectively inhibited the insulin-mediated increase in alpha-class GST expression and GST activity toward NBD. |
| 626 | 16293713 | In contrast, PD98059 (2'-amino-3'-methoxyflavone), an inhibitor of mitogen-activated protein kinase kinase, SP600125 (1,9-pyrazoloanthrone), an inhibitor of c-Jun N-terminal kinase, SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imadazole], an inhibitor of p38 mitogen-activated protein kinase, or bisindolylmaleimide, a broad spectrum inhibitor of protein kinase C, did not inhibit the insulin-mediated increase in alpha-class GST protein levels in hepatocytes. |
| 627 | 16293713 | These results show that PI3K/Akt/p70S6K signaling is active in the insulin-mediated up-regulation of the antioxidant defense system and that low insulin levels, as encountered in diabetes, potentially increase the susceptibility of hepatocytes to xenobiotic-mediated and/or oxidative stress-mediated damage. |
| 628 | 16446424 | Activation of the phosphatidylinositol 3-kinase (PI3K)-AKT/protein kinase B signaling pathway has been associated with multiple human cancers. |
| 629 | 16446424 | Recently we showed that AKT is activated in both the thyroid and metastatic lesions of a mouse model of follicular thyroid carcinoma [thyroid hormone beta receptor (TRbeta)(PV/PV) mice]. |
| 630 | 16446424 | Here we show that in thyroid tumors, PV mutant bound significantly more to the PI3K-regulatory subunit p85alpha, resulting in a greater increase in the kinase activity than did TRbeta1 in wild-type mice. |
| 631 | 16446424 | By confocal fluorescence microscopy, p85alpha was shown to colocalize with TRbeta1 or PV mainly in the nuclear compartment of cultured tumor cells from TRbeta(PV/PV) mice, but cytoplasmic p85alpha/PV or p85alpha/TRbeta1 complexes were also detectable. |
| 632 | 16446424 | Further biochemical analysis revealed that the activation of the PI3K-AKT-mammalian target of the rapamycin-p70(S6K) pathway was observed in both the cytoplasmic and nuclear compartments, whereas the activation of the PI3K-integrin-linked kinase-matrix metalloproteinase 2 pathway was detected mainly in the extranuclear compartments. |
| 633 | 16446424 | These results suggest that PV, via the activation of p85alpha, could act to affect PI3K downstream signaling in both the nuclear and extranuclear compartments, thereby contributing to thyroid carcinogenesis. |
| 634 | 16753575 | Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. |
| 635 | 16753575 | Recent studies have revealed that ribosomal protein S6 kinase 1, S6K1, an effector of mTOR, is sensitive to both insulin and nutrients, including amino acids. |
| 636 | 16753575 | Although S6K1 is an effector of growth, recent reports show that amino acids also negatively affect insulin signaling through mTOR/S6K1 phosphorylation of IRS1. |
| 637 | 16753575 | Moreover, rather than signaling through the class 1 PI3K pathway, amino acids appear to mediate mTOR activation through class 3 PI3K, or hVps34. |
| 638 | 16753575 | Consistent with this, infusion of amino acids into humans leads to S6K1 activation, inhibition of insulin-induced class 1 PI3K activation, and insulin resistance. |
| 639 | 16753575 | Thus, S6K1 may mediate deleterious effects, like insulin resistance, and potentially type 2 diabetes in the face of nutrient excess. |
| 640 | 16753575 | Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. |
| 641 | 16753575 | Recent studies have revealed that ribosomal protein S6 kinase 1, S6K1, an effector of mTOR, is sensitive to both insulin and nutrients, including amino acids. |
| 642 | 16753575 | Although S6K1 is an effector of growth, recent reports show that amino acids also negatively affect insulin signaling through mTOR/S6K1 phosphorylation of IRS1. |
| 643 | 16753575 | Moreover, rather than signaling through the class 1 PI3K pathway, amino acids appear to mediate mTOR activation through class 3 PI3K, or hVps34. |
| 644 | 16753575 | Consistent with this, infusion of amino acids into humans leads to S6K1 activation, inhibition of insulin-induced class 1 PI3K activation, and insulin resistance. |
| 645 | 16753575 | Thus, S6K1 may mediate deleterious effects, like insulin resistance, and potentially type 2 diabetes in the face of nutrient excess. |
| 646 | 16753575 | Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. |
| 647 | 16753575 | Recent studies have revealed that ribosomal protein S6 kinase 1, S6K1, an effector of mTOR, is sensitive to both insulin and nutrients, including amino acids. |
| 648 | 16753575 | Although S6K1 is an effector of growth, recent reports show that amino acids also negatively affect insulin signaling through mTOR/S6K1 phosphorylation of IRS1. |
| 649 | 16753575 | Moreover, rather than signaling through the class 1 PI3K pathway, amino acids appear to mediate mTOR activation through class 3 PI3K, or hVps34. |
| 650 | 16753575 | Consistent with this, infusion of amino acids into humans leads to S6K1 activation, inhibition of insulin-induced class 1 PI3K activation, and insulin resistance. |
| 651 | 16753575 | Thus, S6K1 may mediate deleterious effects, like insulin resistance, and potentially type 2 diabetes in the face of nutrient excess. |
| 652 | 16753575 | Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. |
| 653 | 16753575 | Recent studies have revealed that ribosomal protein S6 kinase 1, S6K1, an effector of mTOR, is sensitive to both insulin and nutrients, including amino acids. |
| 654 | 16753575 | Although S6K1 is an effector of growth, recent reports show that amino acids also negatively affect insulin signaling through mTOR/S6K1 phosphorylation of IRS1. |
| 655 | 16753575 | Moreover, rather than signaling through the class 1 PI3K pathway, amino acids appear to mediate mTOR activation through class 3 PI3K, or hVps34. |
| 656 | 16753575 | Consistent with this, infusion of amino acids into humans leads to S6K1 activation, inhibition of insulin-induced class 1 PI3K activation, and insulin resistance. |
| 657 | 16753575 | Thus, S6K1 may mediate deleterious effects, like insulin resistance, and potentially type 2 diabetes in the face of nutrient excess. |
| 658 | 16753575 | Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. |
| 659 | 16753575 | Recent studies have revealed that ribosomal protein S6 kinase 1, S6K1, an effector of mTOR, is sensitive to both insulin and nutrients, including amino acids. |
| 660 | 16753575 | Although S6K1 is an effector of growth, recent reports show that amino acids also negatively affect insulin signaling through mTOR/S6K1 phosphorylation of IRS1. |
| 661 | 16753575 | Moreover, rather than signaling through the class 1 PI3K pathway, amino acids appear to mediate mTOR activation through class 3 PI3K, or hVps34. |
| 662 | 16753575 | Consistent with this, infusion of amino acids into humans leads to S6K1 activation, inhibition of insulin-induced class 1 PI3K activation, and insulin resistance. |
| 663 | 16753575 | Thus, S6K1 may mediate deleterious effects, like insulin resistance, and potentially type 2 diabetes in the face of nutrient excess. |
| 664 | 16962100 | Acetaldehyde promotes rapamycin-dependent activation of p70(S6K) and glucose uptake despite inhibition of Akt and mTOR in dopaminergic SH-SY5Y human neuroblastoma cells. |
| 665 | 16962100 | Akt, mammalian target of rapamycin (mTOR), ribosomal-S6 kinase (p70(S6K)), the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and insulin receptor substrate (IRS)-2 were evaluated by Western blot analysis. |
| 666 | 16962100 | Short-term exposure (12 h) of acetaldehyde (150 muM) facilitated glucose uptake in a rapamycin-dependent manner without affecting apoptosis, IRS-2 expression and insulin-stimulated glucose uptake in SH-SY5Y cells. |
| 667 | 16962100 | Acetaldehyde suppressed basal and insulin-stimulated Akt phosphorylation without affecting total Akt expression. |
| 668 | 16962100 | Rapamycin, which inhibits mTOR leading to inactivation of p70(S6K), did not affect acetaldehyde-induced inhibition on phosphorylation of Akt and mTOR. |
| 669 | 16962100 | Interestingly, acetaldehyde enhanced p70(S6K) activation and depressed 4E-BP1 phosphorylation, the effect of which was blunted and exaggerated, respectively, by rapamycin. |
| 670 | 16962100 | Collectively, these data suggested that acetaldehyde did not adversely affect glucose uptake despite inhibition of insulin signaling cascade at the levels of Akt and mTOR, possibly due to presence of certain mechanism(s) responsible for enhanced p70(S6K) phosphorylation. |
| 671 | 16962100 | Acetaldehyde promotes rapamycin-dependent activation of p70(S6K) and glucose uptake despite inhibition of Akt and mTOR in dopaminergic SH-SY5Y human neuroblastoma cells. |
| 672 | 16962100 | Akt, mammalian target of rapamycin (mTOR), ribosomal-S6 kinase (p70(S6K)), the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and insulin receptor substrate (IRS)-2 were evaluated by Western blot analysis. |
| 673 | 16962100 | Short-term exposure (12 h) of acetaldehyde (150 muM) facilitated glucose uptake in a rapamycin-dependent manner without affecting apoptosis, IRS-2 expression and insulin-stimulated glucose uptake in SH-SY5Y cells. |
| 674 | 16962100 | Acetaldehyde suppressed basal and insulin-stimulated Akt phosphorylation without affecting total Akt expression. |
| 675 | 16962100 | Rapamycin, which inhibits mTOR leading to inactivation of p70(S6K), did not affect acetaldehyde-induced inhibition on phosphorylation of Akt and mTOR. |
| 676 | 16962100 | Interestingly, acetaldehyde enhanced p70(S6K) activation and depressed 4E-BP1 phosphorylation, the effect of which was blunted and exaggerated, respectively, by rapamycin. |
| 677 | 16962100 | Collectively, these data suggested that acetaldehyde did not adversely affect glucose uptake despite inhibition of insulin signaling cascade at the levels of Akt and mTOR, possibly due to presence of certain mechanism(s) responsible for enhanced p70(S6K) phosphorylation. |
| 678 | 16962100 | Acetaldehyde promotes rapamycin-dependent activation of p70(S6K) and glucose uptake despite inhibition of Akt and mTOR in dopaminergic SH-SY5Y human neuroblastoma cells. |
| 679 | 16962100 | Akt, mammalian target of rapamycin (mTOR), ribosomal-S6 kinase (p70(S6K)), the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and insulin receptor substrate (IRS)-2 were evaluated by Western blot analysis. |
| 680 | 16962100 | Short-term exposure (12 h) of acetaldehyde (150 muM) facilitated glucose uptake in a rapamycin-dependent manner without affecting apoptosis, IRS-2 expression and insulin-stimulated glucose uptake in SH-SY5Y cells. |
| 681 | 16962100 | Acetaldehyde suppressed basal and insulin-stimulated Akt phosphorylation without affecting total Akt expression. |
| 682 | 16962100 | Rapamycin, which inhibits mTOR leading to inactivation of p70(S6K), did not affect acetaldehyde-induced inhibition on phosphorylation of Akt and mTOR. |
| 683 | 16962100 | Interestingly, acetaldehyde enhanced p70(S6K) activation and depressed 4E-BP1 phosphorylation, the effect of which was blunted and exaggerated, respectively, by rapamycin. |
| 684 | 16962100 | Collectively, these data suggested that acetaldehyde did not adversely affect glucose uptake despite inhibition of insulin signaling cascade at the levels of Akt and mTOR, possibly due to presence of certain mechanism(s) responsible for enhanced p70(S6K) phosphorylation. |
| 685 | 16962100 | Acetaldehyde promotes rapamycin-dependent activation of p70(S6K) and glucose uptake despite inhibition of Akt and mTOR in dopaminergic SH-SY5Y human neuroblastoma cells. |
| 686 | 16962100 | Akt, mammalian target of rapamycin (mTOR), ribosomal-S6 kinase (p70(S6K)), the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and insulin receptor substrate (IRS)-2 were evaluated by Western blot analysis. |
| 687 | 16962100 | Short-term exposure (12 h) of acetaldehyde (150 muM) facilitated glucose uptake in a rapamycin-dependent manner without affecting apoptosis, IRS-2 expression and insulin-stimulated glucose uptake in SH-SY5Y cells. |
| 688 | 16962100 | Acetaldehyde suppressed basal and insulin-stimulated Akt phosphorylation without affecting total Akt expression. |
| 689 | 16962100 | Rapamycin, which inhibits mTOR leading to inactivation of p70(S6K), did not affect acetaldehyde-induced inhibition on phosphorylation of Akt and mTOR. |
| 690 | 16962100 | Interestingly, acetaldehyde enhanced p70(S6K) activation and depressed 4E-BP1 phosphorylation, the effect of which was blunted and exaggerated, respectively, by rapamycin. |
| 691 | 16962100 | Collectively, these data suggested that acetaldehyde did not adversely affect glucose uptake despite inhibition of insulin signaling cascade at the levels of Akt and mTOR, possibly due to presence of certain mechanism(s) responsible for enhanced p70(S6K) phosphorylation. |
| 692 | 16962100 | Acetaldehyde promotes rapamycin-dependent activation of p70(S6K) and glucose uptake despite inhibition of Akt and mTOR in dopaminergic SH-SY5Y human neuroblastoma cells. |
| 693 | 16962100 | Akt, mammalian target of rapamycin (mTOR), ribosomal-S6 kinase (p70(S6K)), the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and insulin receptor substrate (IRS)-2 were evaluated by Western blot analysis. |
| 694 | 16962100 | Short-term exposure (12 h) of acetaldehyde (150 muM) facilitated glucose uptake in a rapamycin-dependent manner without affecting apoptosis, IRS-2 expression and insulin-stimulated glucose uptake in SH-SY5Y cells. |
| 695 | 16962100 | Acetaldehyde suppressed basal and insulin-stimulated Akt phosphorylation without affecting total Akt expression. |
| 696 | 16962100 | Rapamycin, which inhibits mTOR leading to inactivation of p70(S6K), did not affect acetaldehyde-induced inhibition on phosphorylation of Akt and mTOR. |
| 697 | 16962100 | Interestingly, acetaldehyde enhanced p70(S6K) activation and depressed 4E-BP1 phosphorylation, the effect of which was blunted and exaggerated, respectively, by rapamycin. |
| 698 | 16962100 | Collectively, these data suggested that acetaldehyde did not adversely affect glucose uptake despite inhibition of insulin signaling cascade at the levels of Akt and mTOR, possibly due to presence of certain mechanism(s) responsible for enhanced p70(S6K) phosphorylation. |
| 699 | 17041622 | Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase. |
| 700 | 17041622 | Raptor is the substrate binding element of TORC1, and the ability of raptor to properly present substrates, such as the translational regulators 4E-BP and p70 S6 kinase, to the TOR catalytic domain is essential for their TOR-catalysed phosphorylation, and is inhibited by the Rapamycin/FKBP-12 complex. |
| 701 | 17041622 | Insulin/IGF enhances Rheb GTP charging through the ability of activated Akt to inhibit the Rheb-GTPase-activating function of the tuberous sclerosis heterodimer (TSC1/TSC2). |
| 702 | 17041622 | Conversely, energy depletion reduces Rheb-GTP charging through the ability of the adenosine monophosphate-activated protein kinase to phosphorylate TSC2 and stimulate its Rheb-GTPase activating function, as well as by HIFalpha-mediated transcriptional responses that act upstream of the TSC1/2 complex. |
| 703 | 17041622 | Amino-acid depletion inhibits TORC1 acting predominantly downstream of the TSC complex, by interfering with the ability of Rheb to bind to mTOR. |
| 704 | 17063460 | Molecular determinants of FGF-21 activity-synergy and cross-talk with PPARgamma signaling. |
| 705 | 17063460 | Here we describe the early signaling events triggered by FGF-21 treatment of 3T3-L1 adipocytes and reveal a functional interplay between FGF-21 and peroxisome proliferator-activated receptor gamma (PPARgamma) pathways that leads to a marked stimulation of glucose transport. |
| 706 | 17063460 | While the early actions of FGF-21 on 3T3-L1 adipocytes involve rapid accumulation of intracellular calcium and phosphorylation of Akt, GSK-3, p70(S6K), SHP-2, MEK1/2, and Stat3, continuous treatment for 72 h induces an increase in PPARgamma protein expression. |
| 707 | 17063460 | Moreover, chronic activation of the PPARgamma pathway in 3T3-L1 adipocytes with the PPARgamma agonist and anti-diabetic agent, rosiglitazone (BRL 49653), enhances FGF-21 action to induce tyrosine phosphorylation of FGF receptor-2. |
| 708 | 17063460 | Strikingly, treatment of cells with FGF-21 and rosiglitazone in combination leads to a pronounced increase in expression of the GLUT1 glucose transporter and a marked synergy in stimulation of glucose transport. |
| 709 | 17063460 | Together these results reveal a novel synergy between two regulators of glucose homeostasis, FGF-21 and PPARgamma, and further define FGF-21 mechanism of action. |
| 710 | 17077083 | Interaction of FoxO1 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway. |
| 711 | 17077083 | Both TSC2 (tuberin) and forkhead transcription factor FoxO1 are phosphorylated and inhibited by Akt and play important roles in insulin signaling. |
| 712 | 17077083 | However, little is known about the relationship between TSC2 and FoxO1. |
| 713 | 17077083 | Here we identified TSC2 as a FoxO1-binding protein by using a yeast two-hybrid screening with a murine islet cDNA library. |
| 714 | 17077083 | Among FoxOs, only FoxO1 can be associated with TSC2. |
| 715 | 17077083 | The physical association between the C terminus of TSC2 (amino acids 1280-1499) and FoxO1 degrades the TSC1-TSC2 complex and inhibits GTPase-activating protein activity of TSC2 toward Rheb. |
| 716 | 17077083 | Overexpression of wild type FoxO1 enhances p70 S6K phosphorylation, whereas overexpression of TSC2 can reverse these effects. |
| 717 | 17077083 | Knockdown of endogenous FOXO1 in human vascular endothelial cells decreased phosphorylation of p70 S6K. |
| 718 | 17077083 | Prolonged overexpression of wild type FoxO1 enhanced phosphorylation of serine 307 of IRS1 and decreased phosphorylation of Akt and FoxO1 itself even in the presence of serum. |
| 719 | 17077083 | These data suggest a novel mechanism by which FoxO1 regulates the insulin signaling pathway through negative regulation of TSC2 function. |
| 720 | 17077083 | Interaction of FoxO1 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway. |
| 721 | 17077083 | Both TSC2 (tuberin) and forkhead transcription factor FoxO1 are phosphorylated and inhibited by Akt and play important roles in insulin signaling. |
| 722 | 17077083 | However, little is known about the relationship between TSC2 and FoxO1. |
| 723 | 17077083 | Here we identified TSC2 as a FoxO1-binding protein by using a yeast two-hybrid screening with a murine islet cDNA library. |
| 724 | 17077083 | Among FoxOs, only FoxO1 can be associated with TSC2. |
| 725 | 17077083 | The physical association between the C terminus of TSC2 (amino acids 1280-1499) and FoxO1 degrades the TSC1-TSC2 complex and inhibits GTPase-activating protein activity of TSC2 toward Rheb. |
| 726 | 17077083 | Overexpression of wild type FoxO1 enhances p70 S6K phosphorylation, whereas overexpression of TSC2 can reverse these effects. |
| 727 | 17077083 | Knockdown of endogenous FOXO1 in human vascular endothelial cells decreased phosphorylation of p70 S6K. |
| 728 | 17077083 | Prolonged overexpression of wild type FoxO1 enhanced phosphorylation of serine 307 of IRS1 and decreased phosphorylation of Akt and FoxO1 itself even in the presence of serum. |
| 729 | 17077083 | These data suggest a novel mechanism by which FoxO1 regulates the insulin signaling pathway through negative regulation of TSC2 function. |
| 730 | 17077083 | Interaction of FoxO1 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway. |
| 731 | 17077083 | Both TSC2 (tuberin) and forkhead transcription factor FoxO1 are phosphorylated and inhibited by Akt and play important roles in insulin signaling. |
| 732 | 17077083 | However, little is known about the relationship between TSC2 and FoxO1. |
| 733 | 17077083 | Here we identified TSC2 as a FoxO1-binding protein by using a yeast two-hybrid screening with a murine islet cDNA library. |
| 734 | 17077083 | Among FoxOs, only FoxO1 can be associated with TSC2. |
| 735 | 17077083 | The physical association between the C terminus of TSC2 (amino acids 1280-1499) and FoxO1 degrades the TSC1-TSC2 complex and inhibits GTPase-activating protein activity of TSC2 toward Rheb. |
| 736 | 17077083 | Overexpression of wild type FoxO1 enhances p70 S6K phosphorylation, whereas overexpression of TSC2 can reverse these effects. |
| 737 | 17077083 | Knockdown of endogenous FOXO1 in human vascular endothelial cells decreased phosphorylation of p70 S6K. |
| 738 | 17077083 | Prolonged overexpression of wild type FoxO1 enhanced phosphorylation of serine 307 of IRS1 and decreased phosphorylation of Akt and FoxO1 itself even in the presence of serum. |
| 739 | 17077083 | These data suggest a novel mechanism by which FoxO1 regulates the insulin signaling pathway through negative regulation of TSC2 function. |
| 740 | 17200203 | Decorin-mediated regulation of fibrillin-1 in the kidney involves the insulin-like growth factor-I receptor and Mammalian target of rapamycin. |
| 741 | 17200203 | Decorin, a small leucine-rich proteoglycan, affects the synthesis of the elastic fiber component fibrillin-1 in the kidney via hitherto unknown mechanisms. |
| 742 | 17200203 | Here, we show that decorin binds to and induces phosphorylation of insulin-like growth factor-I (IGF-I) receptor in renal fibroblasts. |
| 743 | 17200203 | Inhibition of the IGF-I receptor tyrosine kinase and its downstream target phosphoinositide-3 kinase prevented decorin-mediated synthesis of fibrillin-1. |
| 744 | 17200203 | Furthermore, decorin induced phosphorylation of phosphoinositide-dependent kinase 1, protein kinase B/Akt, mammalian target of rapamycin (mTOR), and p70 S6 kinase. |
| 745 | 17200203 | Notably, IGF-I, which signals through the same pathway, also stimulated fibrillin-1 synthesis. |
| 746 | 17200203 | In streptozotocin-induced diabetes, IGF-I receptor was up-regulated in the kidneys from decorin-null mice. |
| 747 | 17200203 | However, this could not compensate for the decorin deficiency, resulting ultimately in decreased fibrillin-1 content. |
| 748 | 17200203 | This study provides evidence for the involvement of decorin and the IGF-I receptor/mTOR/p70 S6 kinase signaling pathway in the translational regulation of fibrillin-1. |
| 749 | 17273556 | Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2. |
| 750 | 17273556 | We report that the combined disruption of 4E-BP1 and 4E-BP2 in mice increased their sensitivity to diet-induced obesity. |
| 751 | 17273556 | Increased adiposity was explained at least in part by accelerated adipogenesis driven by increased expression of CCAAT/enhancer-binding protein delta (C/EBPdelta), C/EBPalpha, and PPARgamma coupled with reduced energy expenditure, reduced lipolysis, and greater fatty acid reesterification in the adipose tissue of 4E-BP1 and 4E-BP2 double KO mice. |
| 752 | 17273556 | Increased insulin resistance in 4E-BP1 and 4E-BP2 double KO mice was associated with increased ribosomal protein S6 kinase (S6K) activity and impairment of Akt signaling in muscle, liver, and adipose tissue. |
| 753 | 17329620 | An amino acid mixture was infused to activate mTOR, and somatostatin-insulin-glucose clamps created conditions of low peripheral hyperinsulinemia (approximately 100 pmol/l, 0-180 min) and prandial-like peripheral hyperinsulinemia (approximately 450 pmol/l, 180-360 min). |
| 754 | 17329620 | In conclusion, rapamycin stimulates insulin-mediated glucose uptake in man under conditions known to activate the mTOR/S6K pathway. |
| 755 | 17459944 | In addition, insulin treatment promoted the formation of large, elongate ASM cells, characterized by dramatic accumulation of contractile phenotype marker proteins and phosphorylated p70(S6K) (downstream target of PI 3-kinase associated with ASM maturation). |
| 756 | 17545163 | Protein-tyrosine phosphatase 1B deficiency reduces insulin resistance and the diabetic phenotype in mice with polygenic insulin resistance. |
| 757 | 17545163 | Protein-tyrosine phosphatase 1B (PTP1B) dephosphorylates tyrosine residues in IR and possibly IRS proteins, thereby inhibiting insulin signaling. |
| 758 | 17545163 | Mice lacking PTP1B are lean and have increased insulin sensitivity. |
| 759 | 17545163 | To determine whether PTP1B can modify polygenic insulin resistance, we crossed PTP1B-/- mice with mice with a double heterozygous deficiency of IR and IRS-1 alleles (DHet). |
| 760 | 17545163 | However, absence of PTP1B in DHet mice markedly improved glucose tolerance and insulin sensitivity at 10-11 weeks of age and reduced the incidence of diabetes and hyperplastic pancreatic islets at 6 months of age. |
| 761 | 17545163 | Insulin-stimulated phosphorylation of IR, IRS proteins, Akt/protein kinase B, glycogen synthase kinase 3beta, and p70(S6K) was impaired in DHet mouse muscle and liver and was differentially improved by PTP1B deficiency. |
| 762 | 17545163 | In summary, PTP1B deficiency reduces insulin resistance and hyperglycemia without altering body weight in a model of polygenic type 2 diabetes. |
| 763 | 17659259 | The contribution of nutrient overload and associated inflammation to insulin resistance has highlighted several therapeutic targets including c-Jun N-terminal kinase (JNK) and S6 kinase (S6K). |
| 764 | 17659259 | Administration of 0.06-4 mg/kg LPS to C57BL/6 mice stimulated increases in plasma levels of TNFalpha, IL-12p40, IL-6 and MCP-1 and in JNK activity as measured by phosphorylated c-Jun in fat. |
| 765 | 17659259 | For the first time, we show that LPS induces S6K activity by up to 6.1-fold, as measured by the phosphorylation of S6 ribosomal protein in liver, and increases by up to 1.8-fold, plasma levels of the novel pro-inflammatory cytokine osteopontin which is implicated in the pathogenesis of insulin resistance. |
| 766 | 17659259 | The contribution of nutrient overload and associated inflammation to insulin resistance has highlighted several therapeutic targets including c-Jun N-terminal kinase (JNK) and S6 kinase (S6K). |
| 767 | 17659259 | Administration of 0.06-4 mg/kg LPS to C57BL/6 mice stimulated increases in plasma levels of TNFalpha, IL-12p40, IL-6 and MCP-1 and in JNK activity as measured by phosphorylated c-Jun in fat. |
| 768 | 17659259 | For the first time, we show that LPS induces S6K activity by up to 6.1-fold, as measured by the phosphorylation of S6 ribosomal protein in liver, and increases by up to 1.8-fold, plasma levels of the novel pro-inflammatory cytokine osteopontin which is implicated in the pathogenesis of insulin resistance. |
| 769 | 17698034 | Rat hepatocytes in primary culture exhibited a rightward shift of the insulin dose-response curve for PKB phosphorylation during culture with palmitate. |
| 770 | 17698034 | The insulin-stimulated phosphorylation of GSK-3beta, a metabolic substrate of PKB, was diminished in palmitate hepatocytes. |
| 771 | 17698034 | Metformin treatment of the hepatocytes resulted in activation of the AMP-activated kinase, attenuation of the mTOR/S6K1 pathway, reduction of IRS-1 phosphorylation, and a leftward shift in the insulin dose-response curve for PKB activation. |
| 772 | 17971008 | Effects of decreased insulin-like growth factor-1 stimulation on hypoxia inducible factor 1-alpha protein synthesis and function during cutaneous repair in diabetic mice. |
| 773 | 17971008 | Insulin-like growth factor-1 (Igf-1), a critical mediator of tissue repair, is significantly decreased in diabetic wounds. |
| 774 | 17971008 | The aim of our study was to examine whether the reduced levels of Igf-1 are responsible for the reduction in Hif-1alpha protein synthesis and activity in diabetic wounds. |
| 775 | 17971008 | We provide evidence that Igf-1 regulates Hif-1alpha protein synthesis and activity during wound repair. |
| 776 | 17971008 | In addition, Igf-1 stimulated phosphytidylinositol 3-kinase activity in diabetic fibroblasts, which, in turn, increased activation of the translational regulatory protein, p70 S6 kinase. |
| 777 | 17971008 | Moreover, improved healing of diabetic wounds by addition of recombinant IGF-1 protein was associated with an increase in Hif-1alpha protein synthesis and function in vivo. |
| 778 | 18045951 | Adiponectin signals in prostate cancer cells through Akt to activate the mammalian target of rapamycin pathway. |
| 779 | 18045951 | Adiponectin has received much attention due to its beneficial effects on insulin sensitivity, and epidemiologic studies have further shown an inverse association between adiponectin levels and risk for multiple tumors, which is independent of the IGF system or other risk factors. |
| 780 | 18045951 | Previous studies have shown that adiponectin can activate AMP-activated protein kinase (AMPK) in myocytes, hepatocytes, and adipocytes, suggesting that adiponectin may suppress tumor development through AMPK activation and subsequent inhibition of mammalian target of rapamycin (mTOR). |
| 781 | 18045951 | In the present study, we demonstrate that while adiponectin stimulates AMPK in phosphatase and tensin homolog deleted on chromosome ten (PTEN) deficient LNCaP prostate cancer cells, it also increases mTOR activity as assessed by phosphorylation of two downstream targets, p70 S6 kinase and ribosomal protein S6. |
| 782 | 18045951 | This adiponectin stimulation of mTOR was mediated through phosphatidylinositol 3-kinase (PI3 kinase) and Akt activation. |
| 783 | 18045951 | These results show that adiponectin can activate both AMPK and PI3 kinase/Akt pathways, and that cell type-specific factors such as PTEN status may determine which of these pathways will have the dominant effect on mTOR. |
| 784 | 18094094 | Pathogenetically, LAM occurs from somatic or genetic mutations of tumor suppressor genes tuberous sclerosis complex 1 (TSC1) or TSC2. |
| 785 | 18094094 | The TSC1/TSC2 protein complex is an integrator of signaling networks regulated by growth factors, insulin, nutrients, and energy. |
| 786 | 18094094 | The observation that the TSC1/TSC2 functions as a negative regulator of the mammalian target of rapamycin (mTOR)/p70 S6 kinase (S6K1) signaling pathway yielded the first rapamycin clinical trial for LAM. |
| 787 | 18094094 | In this article, we will summarize the progress made in our understanding of LAM, and we will focus on how dysregulation of TSC1/TSC2 signaling results in abnormal proliferation and migration of SM-like LAM cells. |
| 788 | 18316403 | Recent studies have demonstrated the importance of insulin or insulin-like growth factor 1 (IGF-1) for regulation of pancreatic beta-cell mass. |
| 789 | 18316403 | Here, we show that mice deficient in TSC2, specifically in pancreatic beta cells (betaTSC2(-/-) mice), manifest increased IGF-1-dependent phosphorylation of p70 S6 kinase and 4E-BP1 in islets as well as an initial increased islet mass attributable in large part to increases in the sizes of individual beta cells. |
| 790 | 18342407 | Amino acids are necessary for the insulin-induced activation of mTOR/S6K1 signaling and protein synthesis in healthy and insulin resistant human skeletal muscle. |
| 791 | 18347057 | Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance. |
| 792 | 18347057 | PDK1 activates a group of kinases, including protein kinase B (PKB)/Akt, p70 ribosomal S6 kinase (S6K), and serum and glucocorticoid-induced protein kinase (SGK), that mediate many of the effects of insulin as well as other agonists. |
| 793 | 18347057 | Activation of PKB is markedly reduced in knock-in mice as a result of lower phosphorylation of PKB at Thr308, the residue phosphorylated by PDK1. |
| 794 | 18347057 | In contrast, activation of SGK1 or p90 ribosomal S6 kinase or stimulation of S6K1 induced by feeding is unaffected by the PDK1 PH domain mutation. |
| 795 | 18347057 | These observations establish the importance of the PDK1-phosphoinositide interaction in enabling PKB to be efficiently activated with an animal model. |
| 796 | 18347057 | Our findings reveal how reduced activation of PKB isoforms impinges on downstream signaling pathways, causing diminution of size as well as insulin resistance. |
| 797 | 18347057 | Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance. |
| 798 | 18347057 | PDK1 activates a group of kinases, including protein kinase B (PKB)/Akt, p70 ribosomal S6 kinase (S6K), and serum and glucocorticoid-induced protein kinase (SGK), that mediate many of the effects of insulin as well as other agonists. |
| 799 | 18347057 | Activation of PKB is markedly reduced in knock-in mice as a result of lower phosphorylation of PKB at Thr308, the residue phosphorylated by PDK1. |
| 800 | 18347057 | In contrast, activation of SGK1 or p90 ribosomal S6 kinase or stimulation of S6K1 induced by feeding is unaffected by the PDK1 PH domain mutation. |
| 801 | 18347057 | These observations establish the importance of the PDK1-phosphoinositide interaction in enabling PKB to be efficiently activated with an animal model. |
| 802 | 18347057 | Our findings reveal how reduced activation of PKB isoforms impinges on downstream signaling pathways, causing diminution of size as well as insulin resistance. |
| 803 | 18374201 | To elucidate the mechanism of diabetic nephropathy, we focus on the role of a vitamin K-dependent growth factor, growth arrest-specific gene 6 (Gas6), and its receptor Axl in the pathogenesis of diabetic nephropathy. |
| 804 | 18374201 | We used streptozotocin (STZ)-induced diabetic rats and mice as a model of diabetic nephropathy and examined the role of Gas6 and Axl in the development of diabetic nephropathy. |
| 805 | 18374201 | After 12 weeks of STZ injection, the glomerular expression of Gas6 and Axl was increased along with the phosphorylation of Akt, p70 S6 kinase, and 4E-BP-1. |
| 806 | 18374201 | Warfarin treatment also inhibited the phosphorylation of Akt, p70 S6 kinase, and 4E-BP-1. |
| 807 | 18374201 | Stimulation of the cells with 25 mmol/l of glucose increased the expression of Gas6/Axl and mesangial cell size compared with that with 5.6 mmol/l of glucose. |
| 808 | 18374201 | LY294002 and rapamycin blocked Gas6-induced activation of the Akt/mTOR pathway and mesangial hypertrophy. |
| 809 | 18374201 | Thus, we have found a novel mechanism of glomerular hypertrophy through the Gas6/Axl-mediated pathway in the development of diabetic nephropathy, where the Akt/mTOR pathway is a key signaling cascade in Gas6-mediated mesangial and glomerular hypertrophy. |
| 810 | 18374201 | Inhibition of the Gas6/Axl pathway in diabetic patients might be beneficial to slow down the progression of diabetic nephropathy. |
| 811 | 18374201 | To elucidate the mechanism of diabetic nephropathy, we focus on the role of a vitamin K-dependent growth factor, growth arrest-specific gene 6 (Gas6), and its receptor Axl in the pathogenesis of diabetic nephropathy. |
| 812 | 18374201 | We used streptozotocin (STZ)-induced diabetic rats and mice as a model of diabetic nephropathy and examined the role of Gas6 and Axl in the development of diabetic nephropathy. |
| 813 | 18374201 | After 12 weeks of STZ injection, the glomerular expression of Gas6 and Axl was increased along with the phosphorylation of Akt, p70 S6 kinase, and 4E-BP-1. |
| 814 | 18374201 | Warfarin treatment also inhibited the phosphorylation of Akt, p70 S6 kinase, and 4E-BP-1. |
| 815 | 18374201 | Stimulation of the cells with 25 mmol/l of glucose increased the expression of Gas6/Axl and mesangial cell size compared with that with 5.6 mmol/l of glucose. |
| 816 | 18374201 | LY294002 and rapamycin blocked Gas6-induced activation of the Akt/mTOR pathway and mesangial hypertrophy. |
| 817 | 18374201 | Thus, we have found a novel mechanism of glomerular hypertrophy through the Gas6/Axl-mediated pathway in the development of diabetic nephropathy, where the Akt/mTOR pathway is a key signaling cascade in Gas6-mediated mesangial and glomerular hypertrophy. |
| 818 | 18374201 | Inhibition of the Gas6/Axl pathway in diabetic patients might be beneficial to slow down the progression of diabetic nephropathy. |
| 819 | 18377870 | Akt activation protects pancreatic beta cells from AMPK-mediated death through stimulation of mTOR. |
| 820 | 18377870 | In pancreatic beta cells this occurs under glucose limitation, or in the presence of the pharmacological AMPK activator 5-aminoimidazole-4-carboxamide-riboside (AICAR). |
| 821 | 18377870 | It is unknown whether Akt activation can counteract AMPK-mediated apoptosis, nor whether mTOR activation downstream of Akt mediates any survival signal in these conditions. |
| 822 | 18377870 | We report that expression of a constitutively active form of Akt increases mTOR activity and prevents apoptosis upon AMPK activation. |
| 823 | 18377870 | Expression of a constitutively active form of the mTOR target ribosomal protein S6 kinase (S6K) or of translation factor eIF4E reduced apoptosis by glucose limitation, and co-expression of S6K and eIF4E protected beta cells to the same extent as active Akt. |
| 824 | 18377870 | The protective effects of active Akt and S6K were associated with increased cellular protein synthesis activity. |
| 825 | 18377870 | It is concluded that Akt stimulation of mTOR and subsequent activation of the targets by which mTOR affects protein translation are required and sufficient mechanisms for Akt-mediated survival of beta cells undergoing sustained AMPK activation. |
| 826 | 18377870 | Akt activation protects pancreatic beta cells from AMPK-mediated death through stimulation of mTOR. |
| 827 | 18377870 | In pancreatic beta cells this occurs under glucose limitation, or in the presence of the pharmacological AMPK activator 5-aminoimidazole-4-carboxamide-riboside (AICAR). |
| 828 | 18377870 | It is unknown whether Akt activation can counteract AMPK-mediated apoptosis, nor whether mTOR activation downstream of Akt mediates any survival signal in these conditions. |
| 829 | 18377870 | We report that expression of a constitutively active form of Akt increases mTOR activity and prevents apoptosis upon AMPK activation. |
| 830 | 18377870 | Expression of a constitutively active form of the mTOR target ribosomal protein S6 kinase (S6K) or of translation factor eIF4E reduced apoptosis by glucose limitation, and co-expression of S6K and eIF4E protected beta cells to the same extent as active Akt. |
| 831 | 18377870 | The protective effects of active Akt and S6K were associated with increased cellular protein synthesis activity. |
| 832 | 18377870 | It is concluded that Akt stimulation of mTOR and subsequent activation of the targets by which mTOR affects protein translation are required and sufficient mechanisms for Akt-mediated survival of beta cells undergoing sustained AMPK activation. |
| 833 | 18430722 | PDK1 regulates cell proliferation and cell cycle progression through control of cyclin D1 and p27Kip1 expression. |
| 834 | 18430722 | The insulin-like growth factor-1-induced phosphorylation of various downstream effectors of PDK1, including Akt, glycogen synthase kinase 3, ribosomal protein S6, and p70 S6 kinase, was markedly inhibited in the PDK1-depleted (Pdk1-KO) MEFs. |
| 835 | 18430722 | These cells also manifested an increased level of p27(Kip1) expression and a reduced level of cyclin D1 expression during cell cycle progression. |
| 836 | 18430722 | The defect in cell cycle progression from the G(0)-G(1) to the S phase in Pdk1-KO MEFs was rescued by forced expression of cyclin D1, whereas rescue of the defect in G(2)-M progression in these cells required both overexpression of cyclin D1 and depletion of p27(Kip1) by RNA interference. |
| 837 | 18430722 | These data indicate that PDK1 plays an important role in cell proliferation and cell cycle progression by controlling the expression of both cyclin D1 and p27(Kip1). |
| 838 | 18618016 | Prolonged activation of p70 S6 kinase (S6K) by insulin and nutrients leads to inhibition of insulin signaling via negative feedback input to the signaling factor IRS-1. |
| 839 | 18713797 | Palmitate also reduced insulin-stimulated IR and IRS-2 tyrosine phosphorylation, IRS-2-associated PI 3-kinase activity, and phosphorylation of Akt, p70 S6 kinase, GSK-3 and FOXO1A. |
| 840 | 18846252 | Akt and S6 kinase (S6K) family members are activated as part of these signaling cascades, but how the interplay between these proteins controls beta cell growth and function has not been determined. |
| 841 | 18846252 | Here, we found that although transgenic mice overexpressing the constitutively active form of Akt1 under the rat insulin promoter (RIP-MyrAkt1 mice) had enlarged beta cells and high plasma insulin levels, leading to improved glucose tolerance, a substantial proportion of the mice developed insulinomas later in life, which caused decreased viability. |
| 842 | 18846252 | To address the role of the mammalian target of rapamycin (mTOR) substrate S6K1 in the MyrAkt1-mediated phenotype, we crossed RIP-MyrAkt1 and S6K1-deficient mice. |
| 843 | 18846252 | Akt and S6 kinase (S6K) family members are activated as part of these signaling cascades, but how the interplay between these proteins controls beta cell growth and function has not been determined. |
| 844 | 18846252 | Here, we found that although transgenic mice overexpressing the constitutively active form of Akt1 under the rat insulin promoter (RIP-MyrAkt1 mice) had enlarged beta cells and high plasma insulin levels, leading to improved glucose tolerance, a substantial proportion of the mice developed insulinomas later in life, which caused decreased viability. |
| 845 | 18846252 | To address the role of the mammalian target of rapamycin (mTOR) substrate S6K1 in the MyrAkt1-mediated phenotype, we crossed RIP-MyrAkt1 and S6K1-deficient mice. |
| 846 | 19035854 | In the present study, we stably co-expressed c-Myc and eGFP [enhanced GFP (green fluorescent protein)] dual-tagged recombinant GLUT4 with recombinant IRS1 (insulin receptor substrate 1) in HEK-293 cells (human embryonic kidney cells) (HEK-293.IRS1.GLUT4 cells). |
| 847 | 19035854 | TRF assays confirmed insulin-stimulated GLUT4 translocation, which can be inhibited by PI3K (phosphoinositide 3-kinase) or Akt [also called PKB (protein kinase B)] inhibitors. |
| 848 | 19035854 | Treatment with palmitate increased IRS1 serine phosphorylation and reduced insulin-stimulated Akt phosphorylation and GLUT4 translocation, indicating insulin resistance. |
| 849 | 19035854 | Knockdown of PTEN (phosphatase and tensin homologue deleted on chromosome 10) and PTP1B (protein tyrosine phosphatase 1B) gene expression by siRNA (small interfering RNA) treatment significantly increased GLUT4 translocation only in cells treated with palmitate but not in untreated cells. |
| 850 | 19035854 | Similar results were obtained on treatment with siRNA of JNK1 (c-Jun N-terminal kinase 1), S6K1 (ribosomal protein S6 kinase, 70 kDa, polypeptide 1) and PKC(theta) (protein kinase C theta). |
| 851 | 19276091 | Targeted disruption of ROCK1 causes insulin resistance in vivo. |
| 852 | 19276091 | Rho-kinase (ROCK) isoforms have been shown to participate in insulin signaling and glucose metabolism in cultured cell lines. |
| 853 | 19276091 | To investigate the physiological role of ROCK1 in the regulation of whole body glucose homeostasis and insulin sensitivity in vivo, we studied mice with global disruption of ROCK1. |
| 854 | 19276091 | Interestingly, ROCK1 gene ablation caused a significant increase in glucose-induced insulin secretion, leading to hyperinsulinemia. |
| 855 | 19276091 | To determine the mechanism(s) by which deletion of ROCK1 causes insulin resistance, we measured the ability of insulin to activate phosphatidylinositol 3-kinase and multiple distal pathways in skeletal muscle. |
| 856 | 19276091 | Insulin-stimulated phosphatidylinositol 3-kinase activity associated with IRS-1 or phospho-tyrosine was also reduced approximately 40% without any alteration in tyrosine phosphorylation of insulin receptor in skeletal muscle. |
| 857 | 19276091 | Insulin-induced phosphorylation of Akt, AS160, S6K, and S6 was also decreased in skeletal muscle. |
| 858 | 19276091 | These data suggest that ROCK1 deficiency causes systemic insulin resistance by impairing insulin signaling in skeletal muscle. |
| 859 | 19276091 | Thus, our results identify ROCK1 as a novel regulator of glucose homeostasis and insulin sensitivity in vivo, which could lead to new treatment approaches for obesity and type 2 diabetes. |
| 860 | 19474189 | In wild-type mice, hypertrophic stimuli increased phosphorylation of 40S ribosomal protein S6 (rpS6), a known target of S6K1. |
| 861 | 19474189 | Immunoblotting analysis revealed that S6K1(-/-) mice exhibited moderately elevated basal levels of rpS6, which did not increase further in response to the hypertrophic stimuli. |
| 862 | 19474189 | Northern blotting indicated a moderate upregulation of S6K2 expression in the kidneys of S6K1(-/-) mice. |
| 863 | 19474189 | Phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1, another downstream target of the mammalian target of rapamycin (mTOR), was stimulated to equivalent levels in S6K1(-/-) and S6K1(+/+) littermates during renal hypertrophy, indicating that mTOR was still activated in the S6K1(-/-) mice. |
| 864 | 19474189 | The highly selective mTOR inhibitor, rapamycin, inhibited increased phosphorylation of rpS6 and blocked 60-70% of the hypertrophy seen in wild-type mice but failed to prevent the approximately 10% hypertrophy seen in S6K1(-/-) mice in response to uninephrectomy (UNX) although it did inhibit the basal rpS6 phosphorylation. |
| 865 | 19474189 | Thus the present study provides the first genetic evidence that S6K1 plays a major role in the development of compensatory renal hypertrophy as well as diabetic renal hypertrophy and indicates that UNX- and diabetes-mediated mTOR activation can selectively activate S6K1 without activating S6K2. |
| 866 | 19474189 | In wild-type mice, hypertrophic stimuli increased phosphorylation of 40S ribosomal protein S6 (rpS6), a known target of S6K1. |
| 867 | 19474189 | Immunoblotting analysis revealed that S6K1(-/-) mice exhibited moderately elevated basal levels of rpS6, which did not increase further in response to the hypertrophic stimuli. |
| 868 | 19474189 | Northern blotting indicated a moderate upregulation of S6K2 expression in the kidneys of S6K1(-/-) mice. |
| 869 | 19474189 | Phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1, another downstream target of the mammalian target of rapamycin (mTOR), was stimulated to equivalent levels in S6K1(-/-) and S6K1(+/+) littermates during renal hypertrophy, indicating that mTOR was still activated in the S6K1(-/-) mice. |
| 870 | 19474189 | The highly selective mTOR inhibitor, rapamycin, inhibited increased phosphorylation of rpS6 and blocked 60-70% of the hypertrophy seen in wild-type mice but failed to prevent the approximately 10% hypertrophy seen in S6K1(-/-) mice in response to uninephrectomy (UNX) although it did inhibit the basal rpS6 phosphorylation. |
| 871 | 19474189 | Thus the present study provides the first genetic evidence that S6K1 plays a major role in the development of compensatory renal hypertrophy as well as diabetic renal hypertrophy and indicates that UNX- and diabetes-mediated mTOR activation can selectively activate S6K1 without activating S6K2. |
| 872 | 19474189 | In wild-type mice, hypertrophic stimuli increased phosphorylation of 40S ribosomal protein S6 (rpS6), a known target of S6K1. |
| 873 | 19474189 | Immunoblotting analysis revealed that S6K1(-/-) mice exhibited moderately elevated basal levels of rpS6, which did not increase further in response to the hypertrophic stimuli. |
| 874 | 19474189 | Northern blotting indicated a moderate upregulation of S6K2 expression in the kidneys of S6K1(-/-) mice. |
| 875 | 19474189 | Phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1, another downstream target of the mammalian target of rapamycin (mTOR), was stimulated to equivalent levels in S6K1(-/-) and S6K1(+/+) littermates during renal hypertrophy, indicating that mTOR was still activated in the S6K1(-/-) mice. |
| 876 | 19474189 | The highly selective mTOR inhibitor, rapamycin, inhibited increased phosphorylation of rpS6 and blocked 60-70% of the hypertrophy seen in wild-type mice but failed to prevent the approximately 10% hypertrophy seen in S6K1(-/-) mice in response to uninephrectomy (UNX) although it did inhibit the basal rpS6 phosphorylation. |
| 877 | 19474189 | Thus the present study provides the first genetic evidence that S6K1 plays a major role in the development of compensatory renal hypertrophy as well as diabetic renal hypertrophy and indicates that UNX- and diabetes-mediated mTOR activation can selectively activate S6K1 without activating S6K2. |
| 878 | 19474189 | In wild-type mice, hypertrophic stimuli increased phosphorylation of 40S ribosomal protein S6 (rpS6), a known target of S6K1. |
| 879 | 19474189 | Immunoblotting analysis revealed that S6K1(-/-) mice exhibited moderately elevated basal levels of rpS6, which did not increase further in response to the hypertrophic stimuli. |
| 880 | 19474189 | Northern blotting indicated a moderate upregulation of S6K2 expression in the kidneys of S6K1(-/-) mice. |
| 881 | 19474189 | Phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1, another downstream target of the mammalian target of rapamycin (mTOR), was stimulated to equivalent levels in S6K1(-/-) and S6K1(+/+) littermates during renal hypertrophy, indicating that mTOR was still activated in the S6K1(-/-) mice. |
| 882 | 19474189 | The highly selective mTOR inhibitor, rapamycin, inhibited increased phosphorylation of rpS6 and blocked 60-70% of the hypertrophy seen in wild-type mice but failed to prevent the approximately 10% hypertrophy seen in S6K1(-/-) mice in response to uninephrectomy (UNX) although it did inhibit the basal rpS6 phosphorylation. |
| 883 | 19474189 | Thus the present study provides the first genetic evidence that S6K1 plays a major role in the development of compensatory renal hypertrophy as well as diabetic renal hypertrophy and indicates that UNX- and diabetes-mediated mTOR activation can selectively activate S6K1 without activating S6K2. |
| 884 | 19474189 | In wild-type mice, hypertrophic stimuli increased phosphorylation of 40S ribosomal protein S6 (rpS6), a known target of S6K1. |
| 885 | 19474189 | Immunoblotting analysis revealed that S6K1(-/-) mice exhibited moderately elevated basal levels of rpS6, which did not increase further in response to the hypertrophic stimuli. |
| 886 | 19474189 | Northern blotting indicated a moderate upregulation of S6K2 expression in the kidneys of S6K1(-/-) mice. |
| 887 | 19474189 | Phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1, another downstream target of the mammalian target of rapamycin (mTOR), was stimulated to equivalent levels in S6K1(-/-) and S6K1(+/+) littermates during renal hypertrophy, indicating that mTOR was still activated in the S6K1(-/-) mice. |
| 888 | 19474189 | The highly selective mTOR inhibitor, rapamycin, inhibited increased phosphorylation of rpS6 and blocked 60-70% of the hypertrophy seen in wild-type mice but failed to prevent the approximately 10% hypertrophy seen in S6K1(-/-) mice in response to uninephrectomy (UNX) although it did inhibit the basal rpS6 phosphorylation. |
| 889 | 19474189 | Thus the present study provides the first genetic evidence that S6K1 plays a major role in the development of compensatory renal hypertrophy as well as diabetic renal hypertrophy and indicates that UNX- and diabetes-mediated mTOR activation can selectively activate S6K1 without activating S6K2. |
| 890 | 19474189 | In wild-type mice, hypertrophic stimuli increased phosphorylation of 40S ribosomal protein S6 (rpS6), a known target of S6K1. |
| 891 | 19474189 | Immunoblotting analysis revealed that S6K1(-/-) mice exhibited moderately elevated basal levels of rpS6, which did not increase further in response to the hypertrophic stimuli. |
| 892 | 19474189 | Northern blotting indicated a moderate upregulation of S6K2 expression in the kidneys of S6K1(-/-) mice. |
| 893 | 19474189 | Phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1, another downstream target of the mammalian target of rapamycin (mTOR), was stimulated to equivalent levels in S6K1(-/-) and S6K1(+/+) littermates during renal hypertrophy, indicating that mTOR was still activated in the S6K1(-/-) mice. |
| 894 | 19474189 | The highly selective mTOR inhibitor, rapamycin, inhibited increased phosphorylation of rpS6 and blocked 60-70% of the hypertrophy seen in wild-type mice but failed to prevent the approximately 10% hypertrophy seen in S6K1(-/-) mice in response to uninephrectomy (UNX) although it did inhibit the basal rpS6 phosphorylation. |
| 895 | 19474189 | Thus the present study provides the first genetic evidence that S6K1 plays a major role in the development of compensatory renal hypertrophy as well as diabetic renal hypertrophy and indicates that UNX- and diabetes-mediated mTOR activation can selectively activate S6K1 without activating S6K2. |
| 896 | 19683471 | Kinases, including IKKbeta, JNK, ERK, mTOR, and S6K, activated by the inducers of insulin resistance induce uncontrolled IRS serine phosphorylation. |
| 897 | 19683471 | Moreover, IKKbeta/NF-kappaB and JNK1 pathways in myeloid cells represent a core mechanism involved in inflammation linked to obesity. |
| 898 | 19683471 | These kinases are thus potential drug targets against insulin resistance and the targeting of the IKKbeta/NF-kappaB or the JNK pathway may evolve into future diabetes medication. |
| 899 | 19797661 | We show in mice that deletion of ribosomal S6 protein kinase 1 (S6K1), a component of the nutrient-responsive mTOR (mammalian target of rapamycin) signaling pathway, led to increased life span and resistance to age-related pathologies, such as bone, immune, and motor dysfunction and loss of insulin sensitivity. |
| 900 | 19797661 | Deletion of S6K1 induced gene expression patterns similar to those seen in CR or with pharmacological activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a conserved regulator of the metabolic response to CR. |
| 901 | 19797661 | Our results demonstrate that S6K1 influences healthy mammalian life-span and suggest that therapeutic manipulation of S6K1 and AMPK might mimic CR and could provide broad protection against diseases of aging. |
| 902 | 19797661 | We show in mice that deletion of ribosomal S6 protein kinase 1 (S6K1), a component of the nutrient-responsive mTOR (mammalian target of rapamycin) signaling pathway, led to increased life span and resistance to age-related pathologies, such as bone, immune, and motor dysfunction and loss of insulin sensitivity. |
| 903 | 19797661 | Deletion of S6K1 induced gene expression patterns similar to those seen in CR or with pharmacological activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a conserved regulator of the metabolic response to CR. |
| 904 | 19797661 | Our results demonstrate that S6K1 influences healthy mammalian life-span and suggest that therapeutic manipulation of S6K1 and AMPK might mimic CR and could provide broad protection against diseases of aging. |
| 905 | 19797661 | We show in mice that deletion of ribosomal S6 protein kinase 1 (S6K1), a component of the nutrient-responsive mTOR (mammalian target of rapamycin) signaling pathway, led to increased life span and resistance to age-related pathologies, such as bone, immune, and motor dysfunction and loss of insulin sensitivity. |
| 906 | 19797661 | Deletion of S6K1 induced gene expression patterns similar to those seen in CR or with pharmacological activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a conserved regulator of the metabolic response to CR. |
| 907 | 19797661 | Our results demonstrate that S6K1 influences healthy mammalian life-span and suggest that therapeutic manipulation of S6K1 and AMPK might mimic CR and could provide broad protection against diseases of aging. |
| 908 | 20027184 | The family comprises some intensely examined protein kinases (such as Akt, S6K, RSK, MSK, PDK1 and GRK) as well as many less well-studied enzymes (such as SGK, NDR, LATS, CRIK, SGK494, PRKX, PRKY and MAST). |
| 909 | 20087248 | In the last decade new genetic defects have been described in all the levels of the growth hormone-releasing hormone (GH-RH)-GH-IGF (insulin-like growth factor) axis. |
| 910 | 20087248 | Genetic defects in the GHRH and in various parts of the Insulin-like growth factor system have been demonstrated. |
| 911 | 20087248 | In animal models and in humans the importance of the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, TBX19, SOX2 and SOX3 has been extensively studied. |
| 912 | 20087248 | A group of signalling proteins are involved in prenatal (SGA) growth retardation: IRS-1, PDK1, AKT1, and S6K1. |
| 913 | 20133456 | Sequential activation of p38MAPK and LKB1-AMPK-tuberous sclerosis complex 2 (TSC2) as well as significant attenuation of ERK1/2 and mammalian target of rapamycin (mTOR)-p70 S6 kinase 1 (p70S6K1) activation was observed through the brown differentiation process. |
| 914 | 20133456 | An in vivo study showed that prolonged 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR)-induced AMPK activation increases uncoupling protein 1 expression and induces an accumulation of brown adipocytes in white adipose tissue (WAT), as revealed by immunohistology. |
| 915 | 20429048 | Palmitate induced insulin resistance by PKCtheta-dependent activation of mTOR/S6K pathway in C2C12 myotubes. |
| 916 | 20429048 | In this study, we showed that palmitate inhibited the insulin signaling in C2C12 myotubes, accompanied with the enhanced phosphorylation of protein kinase C-theta (PKCΘ). |
| 917 | 20429048 | In addition, the phosphorylation of mTOR and p70 ribosomal S6 kinase (S6K) enhanced by palmitate was attenuated in PKCΘ-deficient C2C12 myotubes and in C2C12 myotubes treated with PKCΘ pseudosubstrate. |
| 918 | 20429048 | Taken together, our results suggested that palmitate-induced insulin resistance in C2C12 myotubes is mediated by PKCΘ/mTOR/S6K pathway. |
| 919 | 20429048 | Palmitate induced insulin resistance by PKCtheta-dependent activation of mTOR/S6K pathway in C2C12 myotubes. |
| 920 | 20429048 | In this study, we showed that palmitate inhibited the insulin signaling in C2C12 myotubes, accompanied with the enhanced phosphorylation of protein kinase C-theta (PKCΘ). |
| 921 | 20429048 | In addition, the phosphorylation of mTOR and p70 ribosomal S6 kinase (S6K) enhanced by palmitate was attenuated in PKCΘ-deficient C2C12 myotubes and in C2C12 myotubes treated with PKCΘ pseudosubstrate. |
| 922 | 20429048 | Taken together, our results suggested that palmitate-induced insulin resistance in C2C12 myotubes is mediated by PKCΘ/mTOR/S6K pathway. |
| 923 | 20429048 | Palmitate induced insulin resistance by PKCtheta-dependent activation of mTOR/S6K pathway in C2C12 myotubes. |
| 924 | 20429048 | In this study, we showed that palmitate inhibited the insulin signaling in C2C12 myotubes, accompanied with the enhanced phosphorylation of protein kinase C-theta (PKCΘ). |
| 925 | 20429048 | In addition, the phosphorylation of mTOR and p70 ribosomal S6 kinase (S6K) enhanced by palmitate was attenuated in PKCΘ-deficient C2C12 myotubes and in C2C12 myotubes treated with PKCΘ pseudosubstrate. |
| 926 | 20429048 | Taken together, our results suggested that palmitate-induced insulin resistance in C2C12 myotubes is mediated by PKCΘ/mTOR/S6K pathway. |
| 927 | 20491627 | Current knowledge indicates that mTOR functions as two distinct multiprotein complexes, mTORC1 and mTORC2. mTORC1 phosphorylates p70 S6 kinase (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), and regulates cell growth, proliferation, and survival by integrating hormones, growth factors, nutrients, stressors and energy signals. |
| 928 | 20563709 | Most of the cellular responses to phosphatidylinositol 3-kinase activation and phosphatidylinositol 3,4,5-trisphosphate production are mediated by the activation of a group of AGC kinases comprising PKB, S6K, RSK, SGK and PKC isoforms, which play essential roles in regulating physiological processes related to cell growth, proliferation, survival and metabolism. |
| 929 | 20585550 | Akt represents a nodal point between the Insulin receptor and TOR signaling, and its activation by phosphorylation controls cell proliferation, cell size, and metabolism. |
| 930 | 20585550 | This feedback inhibition is switched from TORC1 to S6K only in the context of enhanced TORC1 activity, as triggered by mutations in tsc2. |
| 931 | 20739737 | Additionally, stimulation of the AMP-activated Protein Kinase concomitantly inhibited mTOR signaling and cell death, while neither event was affected by overexpression of the NAD+ dependent deacetylase Sirt-1, another cellular sensor of nutrient scarcity. |
| 932 | 20739737 | Taken together these findings point to a key role of the mTOR/S6K cascade in cell damage by excess nutrients and scarcity of growth-factors, a condition shared by diabetes and other ageing-related pathologies. |
| 933 | 20847591 | Forced expression of a constitutively active form of Akt containing a myristoylation signal sequence (MyrAkt) in these cells with the use of an adenoviral vector resulted in the phosphorylation of p70 S6 kinase, a downstream target of mTOR signaling, and this effect was inhibited by rapamycin. |
| 934 | 20847591 | MyrAkt also increased the abundance of SREBP1c mRNA and protein as well as the expression of the SREBP1c target genes for fatty acid synthase and stearoyl-CoA desaturase 1. |
| 935 | 20932932 | The 70kDa ribosomal protein S6 kinases, S6K1 and S6K2 are two highly homologous serine/threonine kinases that are activated in response to growth factors, cytokines and nutrients. |
| 936 | 21103335 | Phosphorylation states of 4E-BP1 and S6K1 following leucine gavage increased 2.0- and 3.5-fold, respectively, in Shams but not in Px. |
| 937 | 21157483 | Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt. |
| 938 | 21178385 | p70 Ribosomal S6 kinase 1 (S6K1) is implicated in the pathogenesis of type 2 diabetes as knockout mice are hypoinsulinemic, hypersensitive to insulin treatment and are less susceptible to obesity-induced insulin resistance. |
| 939 | 21178385 | Male rats treated with S6K1 ASO (25 or 50 mg/kg, 2×/week × 4 weeks) had a marked reduction (>90%) of S6K1 mRNA in the liver and epididymal fat and no effect on hepatic S6K2 expression. |
| 940 | 21178385 | These results suggest that inhibition of S6K1 for up to 4 weeks may be therapeutically relevant to induce insulin sensitization and attenuate weight gain with low risk for serious toxicity. |
| 941 | 21178385 | p70 Ribosomal S6 kinase 1 (S6K1) is implicated in the pathogenesis of type 2 diabetes as knockout mice are hypoinsulinemic, hypersensitive to insulin treatment and are less susceptible to obesity-induced insulin resistance. |
| 942 | 21178385 | Male rats treated with S6K1 ASO (25 or 50 mg/kg, 2×/week × 4 weeks) had a marked reduction (>90%) of S6K1 mRNA in the liver and epididymal fat and no effect on hepatic S6K2 expression. |
| 943 | 21178385 | These results suggest that inhibition of S6K1 for up to 4 weeks may be therapeutically relevant to induce insulin sensitization and attenuate weight gain with low risk for serious toxicity. |
| 944 | 21178385 | p70 Ribosomal S6 kinase 1 (S6K1) is implicated in the pathogenesis of type 2 diabetes as knockout mice are hypoinsulinemic, hypersensitive to insulin treatment and are less susceptible to obesity-induced insulin resistance. |
| 945 | 21178385 | Male rats treated with S6K1 ASO (25 or 50 mg/kg, 2×/week × 4 weeks) had a marked reduction (>90%) of S6K1 mRNA in the liver and epididymal fat and no effect on hepatic S6K2 expression. |
| 946 | 21178385 | These results suggest that inhibition of S6K1 for up to 4 weeks may be therapeutically relevant to induce insulin sensitization and attenuate weight gain with low risk for serious toxicity. |
| 947 | 21282364 | Leucine deprivation increases hepatic insulin sensitivity via GCN2/mTOR/S6K1 and AMPK pathways. |
| 948 | 21335550 | FoxO1 activity is tightly controlled by phosphatidylinositol 3-kinase (PI3K) signaling, resulting in its phosphorylation and nuclear exclusion. |
| 949 | 21335550 | We sought here to determine the mechanisms involved in glucose and insulin-stimulated nuclear shuttling of FoxO1 in pancreatic β cells and its consequences for preproinsulin (Ins1, Ins2) gene expression. |
| 950 | 21335550 | Constitutively active PI3K or protein kinase B/Akt exerted similar effects, while inhibitors of PI3K, but not of glycogen synthase kinase-3 or p70 S6 kinase, blocked nuclear export. |
| 951 | 21335550 | FoxO1 overexpression reversed the activation by glucose of pancreatic duodenum homeobox-1 (Pdx1) transcription. |
| 952 | 21335550 | A 915-bp glucose-responsive Ins2 promoter was inhibited by constitutively active FoxO1, an effect unaltered by simultaneous overexpression of PDX1. |
| 953 | 21335550 | We conclude that nuclear import of FoxO1 contributes to the suppression of Pdx1 and Ins2 gene expression at low glucose, the latter via a previously unsuspected and direct physical interaction with the Ins2 promoter. |
| 954 | 21472332 | The HFD animals showed high levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and insulin resistance index (Homa-IR). |
| 955 | 21472332 | Compared with the controls, mRNA levels of mTOR, S6K1, IL-1α, IL-6 and TNFα were significantly increased in the HFD-8 and HFD-16 groups. |
| 956 | 21472332 | The protein levels of mTOR, pmTOR(Ser2448), S6K1, pIRS-1(Ser307), IL-1α and IL-6 were significantly increased in the HFD-8 and HFD-16 groups. |
| 957 | 21472332 | The pIRS-1(Tyr102) level was significantly lower in both the HFD-8 and HFD-16 groups when compared to that in the control group, and the pIRS-1(Tyr102) level was significantly lower in the HFD-16 group compared to that of the HFD-8 group. pmTOR(Ser2448) was positively correlated with the TNFα mRNA level, and pIRS-1(Ser307) was positively correlated with pmTOR(Ser2448), TNFα, S6K1 and mTOR. pIRS-1(Tyr102) was negatively correlated with pmTOR(Ser2448), TNFα, S6K1 and mTOR. |
| 958 | 21472332 | These data indicate that mTOR contributes to insulin resistance and chronic liver inflammation, and may play an important role in the development and progression of NAFLD. |
| 959 | 21472332 | The HFD animals showed high levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and insulin resistance index (Homa-IR). |
| 960 | 21472332 | Compared with the controls, mRNA levels of mTOR, S6K1, IL-1α, IL-6 and TNFα were significantly increased in the HFD-8 and HFD-16 groups. |
| 961 | 21472332 | The protein levels of mTOR, pmTOR(Ser2448), S6K1, pIRS-1(Ser307), IL-1α and IL-6 were significantly increased in the HFD-8 and HFD-16 groups. |
| 962 | 21472332 | The pIRS-1(Tyr102) level was significantly lower in both the HFD-8 and HFD-16 groups when compared to that in the control group, and the pIRS-1(Tyr102) level was significantly lower in the HFD-16 group compared to that of the HFD-8 group. pmTOR(Ser2448) was positively correlated with the TNFα mRNA level, and pIRS-1(Ser307) was positively correlated with pmTOR(Ser2448), TNFα, S6K1 and mTOR. pIRS-1(Tyr102) was negatively correlated with pmTOR(Ser2448), TNFα, S6K1 and mTOR. |
| 963 | 21472332 | These data indicate that mTOR contributes to insulin resistance and chronic liver inflammation, and may play an important role in the development and progression of NAFLD. |
| 964 | 21472332 | The HFD animals showed high levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and insulin resistance index (Homa-IR). |
| 965 | 21472332 | Compared with the controls, mRNA levels of mTOR, S6K1, IL-1α, IL-6 and TNFα were significantly increased in the HFD-8 and HFD-16 groups. |
| 966 | 21472332 | The protein levels of mTOR, pmTOR(Ser2448), S6K1, pIRS-1(Ser307), IL-1α and IL-6 were significantly increased in the HFD-8 and HFD-16 groups. |
| 967 | 21472332 | The pIRS-1(Tyr102) level was significantly lower in both the HFD-8 and HFD-16 groups when compared to that in the control group, and the pIRS-1(Tyr102) level was significantly lower in the HFD-16 group compared to that of the HFD-8 group. pmTOR(Ser2448) was positively correlated with the TNFα mRNA level, and pIRS-1(Ser307) was positively correlated with pmTOR(Ser2448), TNFα, S6K1 and mTOR. pIRS-1(Tyr102) was negatively correlated with pmTOR(Ser2448), TNFα, S6K1 and mTOR. |
| 968 | 21472332 | These data indicate that mTOR contributes to insulin resistance and chronic liver inflammation, and may play an important role in the development and progression of NAFLD. |
| 969 | 21478152 | Resistin promotes cardiac hypertrophy via the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) and c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathways. |
| 970 | 21478152 | Resistin has been suggested to be involved in the development of diabetes and insulin resistance. |
| 971 | 21478152 | Therefore, we wanted to elucidate the mechanisms associated with resistin-induced cardiac hypertrophy and myocardial insulin resistance. |
| 972 | 21478152 | Overexpression of resistin using adenoviral vector in neonatal rat ventricular myocytes was associated with inhibition of AMP-activated protein kinase (AMPK) activity, activation of tuberous sclerosis complex 2/mammalian target of rapamycin (mTOR) pathway, and increased cell size, [(3)H]leucine incorporation (i.e. protein synthesis) and mRNA expression of the hypertrophic marker genes, atrial natriuretic factor, brain natriuretic peptide, and β-myosin heavy chain. |
| 973 | 21478152 | Activation of AMPK with 5-aminoimidazole-4-carbozamide-1-β-D-ribifuranoside or inhibition of mTOR with rapamycin or mTOR siRNA attenuated these resistin-induced changes. |
| 974 | 21478152 | Furthermore, resistin increased serine phosphorylation of insulin receptor substrate (IRS1) through the activation of the apoptosis signal-regulating kinase 1/c-Jun N-terminal Kinase (JNK) pathway, a module known to stimulate insulin resistance. |
| 975 | 21478152 | Inhibition of JNK (with JNK inhibitor SP600125 or using dominant-negative JNK) reduced serine 307 phosphorylation of IRS1. |
| 976 | 21478152 | Resistin also stimulated the activation of p70(S6K), a downstream kinase target of mTOR, and increased phosphorylation of the IRS1 serine 636/639 residues, whereas treatment with rapamycin reduced the phosphorylation of these residues. |
| 977 | 21478152 | These data demonstrate that resistin induces cardiac hypertrophy and myocardial insulin resistance, possibly via the AMPK/mTOR/p70(S6K) and apoptosis signal-regulating kinase 1/JNK/IRS1 pathways. |
| 978 | 21478152 | Resistin promotes cardiac hypertrophy via the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) and c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathways. |
| 979 | 21478152 | Resistin has been suggested to be involved in the development of diabetes and insulin resistance. |
| 980 | 21478152 | Therefore, we wanted to elucidate the mechanisms associated with resistin-induced cardiac hypertrophy and myocardial insulin resistance. |
| 981 | 21478152 | Overexpression of resistin using adenoviral vector in neonatal rat ventricular myocytes was associated with inhibition of AMP-activated protein kinase (AMPK) activity, activation of tuberous sclerosis complex 2/mammalian target of rapamycin (mTOR) pathway, and increased cell size, [(3)H]leucine incorporation (i.e. protein synthesis) and mRNA expression of the hypertrophic marker genes, atrial natriuretic factor, brain natriuretic peptide, and β-myosin heavy chain. |
| 982 | 21478152 | Activation of AMPK with 5-aminoimidazole-4-carbozamide-1-β-D-ribifuranoside or inhibition of mTOR with rapamycin or mTOR siRNA attenuated these resistin-induced changes. |
| 983 | 21478152 | Furthermore, resistin increased serine phosphorylation of insulin receptor substrate (IRS1) through the activation of the apoptosis signal-regulating kinase 1/c-Jun N-terminal Kinase (JNK) pathway, a module known to stimulate insulin resistance. |
| 984 | 21478152 | Inhibition of JNK (with JNK inhibitor SP600125 or using dominant-negative JNK) reduced serine 307 phosphorylation of IRS1. |
| 985 | 21478152 | Resistin also stimulated the activation of p70(S6K), a downstream kinase target of mTOR, and increased phosphorylation of the IRS1 serine 636/639 residues, whereas treatment with rapamycin reduced the phosphorylation of these residues. |
| 986 | 21478152 | These data demonstrate that resistin induces cardiac hypertrophy and myocardial insulin resistance, possibly via the AMPK/mTOR/p70(S6K) and apoptosis signal-regulating kinase 1/JNK/IRS1 pathways. |
| 987 | 21576368 | Mutational analysis of these phosphorylation sites indicates that dual S2159/T2164 phosphorylation cooperatively promotes mTORC1 signaling to S6K1 and 4EBP1. |
| 988 | 21977024 | In conditions of over-nutrition, increased insulin (INS) and angiotensin II (Ang II) activate mammalian target for rapamycin (mTOR)/p70 S6 kinase (S6K1) signaling, whereas chronic alcohol consumption inhibits mTOR/S6K1 activation in cardiac tissue. |
| 989 | 21977024 | Although excessive activation of mTOR/S6K1 induces cardiac INS resistance via serine phosphorylation of INS receptor substrates (IRS-1/2), it also renders cardioprotection via increased Ang II receptor 2 (AT2R) upregulation and adaptive hypertrophy. |
| 990 | 21977024 | Conversely, alcohol-mediated inhibition of mTOR/S6K1, down-regulation of INS receptor and growth-inhibitory mir-200 family, and upregulation of mir-212 that promotes fetal gene program may exacerbate CRS-related cardiomyopathy. |
| 991 | 21977024 | In conditions of over-nutrition, increased insulin (INS) and angiotensin II (Ang II) activate mammalian target for rapamycin (mTOR)/p70 S6 kinase (S6K1) signaling, whereas chronic alcohol consumption inhibits mTOR/S6K1 activation in cardiac tissue. |
| 992 | 21977024 | Although excessive activation of mTOR/S6K1 induces cardiac INS resistance via serine phosphorylation of INS receptor substrates (IRS-1/2), it also renders cardioprotection via increased Ang II receptor 2 (AT2R) upregulation and adaptive hypertrophy. |
| 993 | 21977024 | Conversely, alcohol-mediated inhibition of mTOR/S6K1, down-regulation of INS receptor and growth-inhibitory mir-200 family, and upregulation of mir-212 that promotes fetal gene program may exacerbate CRS-related cardiomyopathy. |
| 994 | 21977024 | In conditions of over-nutrition, increased insulin (INS) and angiotensin II (Ang II) activate mammalian target for rapamycin (mTOR)/p70 S6 kinase (S6K1) signaling, whereas chronic alcohol consumption inhibits mTOR/S6K1 activation in cardiac tissue. |
| 995 | 21977024 | Although excessive activation of mTOR/S6K1 induces cardiac INS resistance via serine phosphorylation of INS receptor substrates (IRS-1/2), it also renders cardioprotection via increased Ang II receptor 2 (AT2R) upregulation and adaptive hypertrophy. |
| 996 | 21977024 | Conversely, alcohol-mediated inhibition of mTOR/S6K1, down-regulation of INS receptor and growth-inhibitory mir-200 family, and upregulation of mir-212 that promotes fetal gene program may exacerbate CRS-related cardiomyopathy. |
| 997 | 22028412 | Activation of mTOR/p70S6 kinase by ANG II inhibits insulin-stimulated endothelial nitric oxide synthase and vasodilation. |
| 998 | 22028412 | Elevated tissue levels of angiotensin II (ANG II) are associated with impairment of insulin actions in metabolic and cardiovascular tissues. |
| 999 | 22028412 | ANG II-stimulated activation of mammalian target of rapamycin (mTOR)/p70 S6 kinase (p70S6K) in cardiovascular tissues is implicated in cardiac hypertrophy and vascular remodeling. |
| 1000 | 22028412 | ANG II increased phosphorylation of insulin receptor substrate-1 (IRS-1) at Ser(636/639) and inhibited the insulin-stimulated phosphorylation of endothelial nitric oxide synthase (eNOS). |
| 1001 | 22028412 | An inhibitor of mTOR, rapamycin, attenuated the ANG II-stimulated phosphorylation of p70S6K and phosphorylation of IRS-1 (Ser(636/639)) and blocked the ability of ANG II to impair insulin-stimulated phosphorylation of eNOS, nitric oxide production, and mesenteric-arteriole vasodilation. |
| 1002 | 22028412 | Moreover, point mutations of IRS-1 at Ser(636/639) to Ala prevented the ANG II-mediated inhibition of insulin signaling. |
| 1003 | 22028412 | From these results, we conclude that activation of mTOR/p70S6K by ANG II in vascular endothelium may contribute to impairment of insulin-stimulated vasodilation through phosphorylation of IRS-1 at Ser(636/639). |
| 1004 | 22028412 | This ANG II-mediated impairment of vascular actions of insulin may help explain the role of ANG II as a link between insulin resistance and hypertension. |
| 1005 | 22065737 | The p70 ribosomal protein S6 kinase 1 (S6K1) plays a key role in cell growth and proliferation by regulating insulin sensitivity, metabolism, protein synthesis, and cell cycle. |
| 1006 | 22087027 | The type 1 insulin-like growth factor receptor (IGF-IR) pathway is mandatory for the follistatin-induced skeletal muscle hypertrophy. |
| 1007 | 22087027 | Myostatin inhibition by follistatin (FS) offers a new approach for muscle mass enhancement. |
| 1008 | 22087027 | Because IGF-I and IGF-II, two crucial skeletal muscle growth factors, are induced by myostatin inhibition, we assessed their role in FS action. |
| 1009 | 22087027 | We then tested the role of the signaling molecules stimulated by IGF-IR, in particular the Akt/mammalian target of rapamycin (mTOR)/70-kDa ribosomal protein S6 kinase (S6K) pathway. |
| 1010 | 22087027 | In conclusion, the IGF-IR/Akt/mTOR pathway plays a critical role in FS-induced muscle hypertrophy. |
| 1011 | 22087027 | In contrast, induction of IGF-II expression and S6K activity by FS are not required for the hypertrophic action of FS. |
| 1012 | 22087027 | The type 1 insulin-like growth factor receptor (IGF-IR) pathway is mandatory for the follistatin-induced skeletal muscle hypertrophy. |
| 1013 | 22087027 | Myostatin inhibition by follistatin (FS) offers a new approach for muscle mass enhancement. |
| 1014 | 22087027 | Because IGF-I and IGF-II, two crucial skeletal muscle growth factors, are induced by myostatin inhibition, we assessed their role in FS action. |
| 1015 | 22087027 | We then tested the role of the signaling molecules stimulated by IGF-IR, in particular the Akt/mammalian target of rapamycin (mTOR)/70-kDa ribosomal protein S6 kinase (S6K) pathway. |
| 1016 | 22087027 | In conclusion, the IGF-IR/Akt/mTOR pathway plays a critical role in FS-induced muscle hypertrophy. |
| 1017 | 22087027 | In contrast, induction of IGF-II expression and S6K activity by FS are not required for the hypertrophic action of FS. |
| 1018 | 22412899 | Comparison of male mice lacking S6K1 and 2 (S6K-dko) with wt controls showed that S6K-dko mice are protected against obesity and glucose intolerance induced by a high-fat diet. |
| 1019 | 22457523 | Hepatitis C virus activates the mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance. |
| 1020 | 22457523 | We have previously shown that HCV infection modulates phosphorylation of Akt, a downstream target of IRS-1. |
| 1021 | 22457523 | In this study, we further examined the status of total IRS-1 and the downstream regulation of the Akt pathway in understanding mTOR/S6K1 signaling using HCV genotype 2a (clone JFH1)-infected hepatocytes. |
| 1022 | 22457523 | The status of the tuberous sclerosis complex (TSC-1/TSC-2) was significantly decreased after HCV infection of human hepatocytes, showing a modulation of the downstream Akt pathway. |
| 1023 | 22457523 | Subsequent study indicated an increased level of Rheb and mTOR expression in HCV-infected hepatocytes. |
| 1024 | 22457523 | Ectopic expression of TSC-1/TSC-2 significantly recovered the IRS-1 protein expression level in HCV-infected hepatocytes. |
| 1025 | 22457523 | Further analyses indicated that HCV core protein plays a significant role in modulating the mTOR/S6K1 signaling pathway. |
| 1026 | 22457523 | Proteasome inhibitor MG 132 recovered IRS-1 and TSC1/2 expression, suggesting that degradation occurred via the ubiquitin proteasome pathway. |
| 1027 | 22457523 | A functional consequence of IRS-1 inhibition was reflected in a decrease in GLUT4 protein expression and upregulation of the gluconeogenic enzyme PCK2 in HCV-infected hepatocytes. |
| 1028 | 22457523 | Together, these observations suggested that HCV infection activates the mTOR/S6K1 pathway in inhibiting IRS-1 function and perturbs glucose metabolism via downregulation of GLUT4 and upregulation of PCK2 for insulin resistance. |
| 1029 | 22457523 | Hepatitis C virus activates the mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance. |
| 1030 | 22457523 | We have previously shown that HCV infection modulates phosphorylation of Akt, a downstream target of IRS-1. |
| 1031 | 22457523 | In this study, we further examined the status of total IRS-1 and the downstream regulation of the Akt pathway in understanding mTOR/S6K1 signaling using HCV genotype 2a (clone JFH1)-infected hepatocytes. |
| 1032 | 22457523 | The status of the tuberous sclerosis complex (TSC-1/TSC-2) was significantly decreased after HCV infection of human hepatocytes, showing a modulation of the downstream Akt pathway. |
| 1033 | 22457523 | Subsequent study indicated an increased level of Rheb and mTOR expression in HCV-infected hepatocytes. |
| 1034 | 22457523 | Ectopic expression of TSC-1/TSC-2 significantly recovered the IRS-1 protein expression level in HCV-infected hepatocytes. |
| 1035 | 22457523 | Further analyses indicated that HCV core protein plays a significant role in modulating the mTOR/S6K1 signaling pathway. |
| 1036 | 22457523 | Proteasome inhibitor MG 132 recovered IRS-1 and TSC1/2 expression, suggesting that degradation occurred via the ubiquitin proteasome pathway. |
| 1037 | 22457523 | A functional consequence of IRS-1 inhibition was reflected in a decrease in GLUT4 protein expression and upregulation of the gluconeogenic enzyme PCK2 in HCV-infected hepatocytes. |
| 1038 | 22457523 | Together, these observations suggested that HCV infection activates the mTOR/S6K1 pathway in inhibiting IRS-1 function and perturbs glucose metabolism via downregulation of GLUT4 and upregulation of PCK2 for insulin resistance. |
| 1039 | 22457523 | Hepatitis C virus activates the mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance. |
| 1040 | 22457523 | We have previously shown that HCV infection modulates phosphorylation of Akt, a downstream target of IRS-1. |
| 1041 | 22457523 | In this study, we further examined the status of total IRS-1 and the downstream regulation of the Akt pathway in understanding mTOR/S6K1 signaling using HCV genotype 2a (clone JFH1)-infected hepatocytes. |
| 1042 | 22457523 | The status of the tuberous sclerosis complex (TSC-1/TSC-2) was significantly decreased after HCV infection of human hepatocytes, showing a modulation of the downstream Akt pathway. |
| 1043 | 22457523 | Subsequent study indicated an increased level of Rheb and mTOR expression in HCV-infected hepatocytes. |
| 1044 | 22457523 | Ectopic expression of TSC-1/TSC-2 significantly recovered the IRS-1 protein expression level in HCV-infected hepatocytes. |
| 1045 | 22457523 | Further analyses indicated that HCV core protein plays a significant role in modulating the mTOR/S6K1 signaling pathway. |
| 1046 | 22457523 | Proteasome inhibitor MG 132 recovered IRS-1 and TSC1/2 expression, suggesting that degradation occurred via the ubiquitin proteasome pathway. |
| 1047 | 22457523 | A functional consequence of IRS-1 inhibition was reflected in a decrease in GLUT4 protein expression and upregulation of the gluconeogenic enzyme PCK2 in HCV-infected hepatocytes. |
| 1048 | 22457523 | Together, these observations suggested that HCV infection activates the mTOR/S6K1 pathway in inhibiting IRS-1 function and perturbs glucose metabolism via downregulation of GLUT4 and upregulation of PCK2 for insulin resistance. |
| 1049 | 22711699 | Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin. |
| 1050 | 22711699 | Furthermore, we identify Smad3 as the critical intracellular link that mediates the effects of follistatin on mTOR signaling. |
| 1051 | 22711699 | Expression of constitutively active Smad3 not only markedly prevented skeletal muscle growth induced by follistatin but also potently suppressed follistatin-induced Akt/mTOR/S6K signaling. |
| 1052 | 22711699 | Importantly, the regulation of Smad3- and mTOR-dependent events by follistatin occurred independently of overexpression or knockout of myostatin, a key repressor of muscle development that can regulate Smad3 and mTOR signaling and that is itself inhibited by follistatin. |
| 1053 | 22711699 | These findings identify a critical role of Smad3/Akt/mTOR/S6K/S6RP signaling in follistatin-mediated muscle growth that operates independently of myostatin-driven mechanisms. |
| 1054 | 22711699 | Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin. |
| 1055 | 22711699 | Furthermore, we identify Smad3 as the critical intracellular link that mediates the effects of follistatin on mTOR signaling. |
| 1056 | 22711699 | Expression of constitutively active Smad3 not only markedly prevented skeletal muscle growth induced by follistatin but also potently suppressed follistatin-induced Akt/mTOR/S6K signaling. |
| 1057 | 22711699 | Importantly, the regulation of Smad3- and mTOR-dependent events by follistatin occurred independently of overexpression or knockout of myostatin, a key repressor of muscle development that can regulate Smad3 and mTOR signaling and that is itself inhibited by follistatin. |
| 1058 | 22711699 | These findings identify a critical role of Smad3/Akt/mTOR/S6K/S6RP signaling in follistatin-mediated muscle growth that operates independently of myostatin-driven mechanisms. |
| 1059 | 22787141 | S6K1 in the central nervous system regulates energy expenditure via MC4R/CRH pathways in response to deprivation of an essential amino acid. |
| 1060 | 22787141 | Furthermore, we show that the effect of hypothalamic S6K1 is mediated by modulation of Crh expression in a melanocortin-4 receptor-dependent manner. |
| 1061 | 22851690 | The combined deletion of S6K1 and Akt2 deteriorates glycemic control in a high-fat diet. |
| 1062 | 22851690 | Signaling downstream of mechanistic target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2) controls specific and distinct aspects of insulin action and nutrient homeostasis in an interconnected and as yet unclear way. |
| 1063 | 22869320 | Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. |
| 1064 | 22869320 | The insulin receptor substrate proteins IRS1 and IRS2 are key targets of the insulin receptor tyrosine kinase and are required for hormonal control of metabolism. |
| 1065 | 22869320 | However, IRS1 and IRS2 are regulated through a complex mechanism involving phosphorylation of >50 serine/threonine residues (S/T) within their long, unstructured tail regions. |
| 1066 | 22869320 | In cultured cells, insulin-stimulated kinases (including atypical PKC, AKT, SIK2, mTOR, S6K1, ERK1/2 and ROCK1) mediate feedback (autologous) S/T phosphorylation of IRS, with both positive and negative effects on insulin sensitivity. |
| 1067 | 22869320 | Additionally, insulin-independent (heterologous) kinases can phosphorylate IRS1/2 under basal conditions (AMPK, GSK3) or in response to sympathetic activation and lipid/inflammatory mediators, which are present at elevated levels in metabolic disease (GRK2, novel and conventional PKCs, JNK, IKKβ, mPLK). |
| 1068 | 23454693 | Central activating transcription factor 4 (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve. |
| 1069 | 23454693 | The aim of our current study is to investigate the possible involvement of hypothalamic activating transcription factor 4 (ATF4) in the regulation of insulin sensitivity in the liver. |
| 1070 | 23454693 | Here, we show that overexpression of ATF4 in the hypothalamus resulting from intracerebroventricular injection of adenovirus expressing ATF4 induces hepatic insulin resistance in mice and that inhibition of hypothalamic ATF4 by intracerebroventricular adenovirus expressing a dominant-negative ATF4 variant has the opposite effect. |
| 1071 | 23454693 | We also show that hypothalamic ATF4-induced insulin resistance is significantly blocked by selective hepatic vagotomy or by inhibiting activity of the mammalian target of rapamycin (mTOR) downstream target S6K1. |
| 1072 | 23454693 | Finally, we show that inhibition of hypothalamic ATF4 reverses hepatic insulin resistance induced by acute brain endoplasmic reticulum (ER) stress. |
| 1073 | 23454693 | Taken together, our study describes a novel central pathway regulating hepatic insulin sensitivity that is mediated by hypothalamic ATF4/mTOR/S6K1 signaling and the vagus nerve and demonstrates an important role for hypothalamic ATF4 in brain ER stress-induced hepatic insulin resistance. |
| 1074 | 23525347 | Small‑molecule COH-SR4 inhibits adipocyte differentiation via AMPK activation. |
| 1075 | 23525347 | AMPK activation by COH-SR4 also resulted in the phosphorylation of raptor and tuberous sclerosis protein 2 (TSC2), two proteins involved in the mammalian target of rapamycin (mTOR) signaling pathways. |
| 1076 | 23525347 | Additionally, COH-SR4 decreased the phosphorylation of p70 kDa ribosomal protein S6 kinase (S6K) and initiation factor 4E (eIF4E) binding protein 1 (4EB‑P1), two downstream effectors of mTOR that regulate protein synthesis. |
| 1077 | 23565163 | Phosphorylation of IRS1 at serine 307 in response to insulin in human adipocytes is not likely to be catalyzed by p70 ribosomal S6 kinase. |
| 1078 | 23565163 | The insulin receptor substrate-1 (IRS1) is phosphorylated on serine 307 (human sequence, corresponding to murine serine 302) in response to insulin as part of a feedback loop that controls IRS1 phosphorylation on tyrosine residues by the insulin receptor. |
| 1079 | 23565163 | The mTORC1-downstream p70 ribosomal protein S6 kinase (S6K1), which is activated by insulin, can phosphorylate IRS1 at serine 307 in vitro and is considered the physiological protein kinase. |
| 1080 | 23565163 | Because the IRS1 serine 307-kinase catalyzes a critical step in the control of insulin signaling and constitutes a potential target for treatment of insulin resistance, it is important to know whether S6K1 is the physiological serine 307-kinase or not. |
| 1081 | 23565163 | We report that, by several criteria, S6K1 does not phosphorylate IRS1 at serine 307 in response to insulin in intact human primary adipocytes: (i) The time-courses for phosphorylation of S6K1 and its phosphorylation of S6 are not compatible with the phosphorylation of IRS1 at serine 307; (ii) A dominant-negative construct of S6K1 inhibits the phosphorylation of S6, without effect on the phosphorylation of IRS1 at serine 307; (iii) The specific inhibitor of S6K1 PF-4708671 inhibits the phosphorylation of S6, without effect on phosphorylation of IRS1 at serine 307. mTOR-immunoprecipitates from insulin-stimulated adipocytes contains an unidentified protein kinase specific for phosphorylation of IRS1 at serine 307, but it is not mTOR or S6K1. |
| 1082 | 23565163 | Phosphorylation of IRS1 at serine 307 in response to insulin in human adipocytes is not likely to be catalyzed by p70 ribosomal S6 kinase. |
| 1083 | 23565163 | The insulin receptor substrate-1 (IRS1) is phosphorylated on serine 307 (human sequence, corresponding to murine serine 302) in response to insulin as part of a feedback loop that controls IRS1 phosphorylation on tyrosine residues by the insulin receptor. |
| 1084 | 23565163 | The mTORC1-downstream p70 ribosomal protein S6 kinase (S6K1), which is activated by insulin, can phosphorylate IRS1 at serine 307 in vitro and is considered the physiological protein kinase. |
| 1085 | 23565163 | Because the IRS1 serine 307-kinase catalyzes a critical step in the control of insulin signaling and constitutes a potential target for treatment of insulin resistance, it is important to know whether S6K1 is the physiological serine 307-kinase or not. |
| 1086 | 23565163 | We report that, by several criteria, S6K1 does not phosphorylate IRS1 at serine 307 in response to insulin in intact human primary adipocytes: (i) The time-courses for phosphorylation of S6K1 and its phosphorylation of S6 are not compatible with the phosphorylation of IRS1 at serine 307; (ii) A dominant-negative construct of S6K1 inhibits the phosphorylation of S6, without effect on the phosphorylation of IRS1 at serine 307; (iii) The specific inhibitor of S6K1 PF-4708671 inhibits the phosphorylation of S6, without effect on phosphorylation of IRS1 at serine 307. mTOR-immunoprecipitates from insulin-stimulated adipocytes contains an unidentified protein kinase specific for phosphorylation of IRS1 at serine 307, but it is not mTOR or S6K1. |
| 1087 | 23565163 | Phosphorylation of IRS1 at serine 307 in response to insulin in human adipocytes is not likely to be catalyzed by p70 ribosomal S6 kinase. |
| 1088 | 23565163 | The insulin receptor substrate-1 (IRS1) is phosphorylated on serine 307 (human sequence, corresponding to murine serine 302) in response to insulin as part of a feedback loop that controls IRS1 phosphorylation on tyrosine residues by the insulin receptor. |
| 1089 | 23565163 | The mTORC1-downstream p70 ribosomal protein S6 kinase (S6K1), which is activated by insulin, can phosphorylate IRS1 at serine 307 in vitro and is considered the physiological protein kinase. |
| 1090 | 23565163 | Because the IRS1 serine 307-kinase catalyzes a critical step in the control of insulin signaling and constitutes a potential target for treatment of insulin resistance, it is important to know whether S6K1 is the physiological serine 307-kinase or not. |
| 1091 | 23565163 | We report that, by several criteria, S6K1 does not phosphorylate IRS1 at serine 307 in response to insulin in intact human primary adipocytes: (i) The time-courses for phosphorylation of S6K1 and its phosphorylation of S6 are not compatible with the phosphorylation of IRS1 at serine 307; (ii) A dominant-negative construct of S6K1 inhibits the phosphorylation of S6, without effect on the phosphorylation of IRS1 at serine 307; (iii) The specific inhibitor of S6K1 PF-4708671 inhibits the phosphorylation of S6, without effect on phosphorylation of IRS1 at serine 307. mTOR-immunoprecipitates from insulin-stimulated adipocytes contains an unidentified protein kinase specific for phosphorylation of IRS1 at serine 307, but it is not mTOR or S6K1. |
| 1092 | 23650507 | However, isolated human islets displayed insulin signaling pathway resistance, due in part to chronic activation of mTOR/S6K1 signaling that results in negative feedback of the insulin signaling pathway and a loss of Akt phosphorylation and insulin content. |
| 1093 | 23650507 | This was associated with the restoration of IGF-1-induced phosphorylation of Akt, GSK-3, and increased protein expression of Pdx1. |
| 1094 | 23650507 | Furthermore, MSDC-0160 in combination with IGF-1 and 8 mM glucose increased β-cell specific gene expression of insulin, pdx1, nkx6.1, and nkx2.2, and maintained insulin content without altering glucose-stimulated insulin secretion. |
| 1095 | 23712034 | Proline-rich Akt substrate of 40-kDa contains a nuclear export signal. |
| 1096 | 23712034 | The proline-rich Akt substrate of 40-kDa (PRAS40) has been linked to the regulation of the activity of the mammalian target of rapamycin complex 1 as well as insulin action. |
| 1097 | 23712034 | Finally, A14 cells expressing the NES-mutant showed impaired activation of components of the Akt-pathway as well as of the mTORC1 substrate p70 S6 kinase after insulin stimulation. |
| 1098 | 23712034 | Furthermore, enforced nuclear accumulation of PRAS40 impairs insulin action, thereby substantiating the function of this protein in the regulation of insulin sensitivity. |
| 1099 | 23922555 | The Novel Angiotensin II Receptor Blocker Azilsartan Medoxomil Ameliorates Insulin Resistance Induced by Chronic Angiotensin II Treatment in Rat Skeletal Muscle. |
| 1100 | 23922555 | Angiotensin receptor (type 1) blockers (ARBs) can reduce both hypertension and insulin resistance induced by local and systemic activation of the renin-angiotensin-aldosterone system. |
| 1101 | 23922555 | The effectiveness of azilsartan medoxomil (AZIL-M), a novel imidazole-based ARB, to facilitate metabolic improvements in conditions of angiotensin II (Ang II)-associated insulin resistance is currently unknown. |
| 1102 | 23922555 | The aim of this study was to determine the impact of chronic AZIL-M treatment on glucose transport activity and key insulin signaling elements in red skeletal muscle of Ang II-treated rats. |
| 1103 | 23922555 | Furthermore, Ang II reduced insulin-mediated glucose transport activity in incubated soleus muscle, and AZIL-M co-treatment increased this parameter. |
| 1104 | 23922555 | Moreover, AZIL-M treatment of Ang II-infused animals increased the absolute phosphorylation of insulin signaling molecules, including Akt [both Ser473 (81%) and Thr308 (23%)] and AS160 Thr642 (42%), in red gastrocnemius muscle frozen in situ. |
| 1105 | 23922555 | Absolute AMPKα (Thr172) phosphorylation increased (98%) by AZIL-M treatment, and relative Thr389 phosphorylation of p70 S6K1, a negative regulator of insulin signaling, decreased (51%) with AZIL-M treatment. |
| 1106 | 23922555 | These results indicate that ARB AZIL-M improves the in vitro insulin action on glucose transport in red soleus muscle and the functionality of the Akt/AS160 axis in red gastrocnemius muscle in situ in Ang II-induced insulin-resistant rats, with the latter modification possibly associated with enhanced AMPKα and suppressed p70 S6K1 activation. |
| 1107 | 23922555 | The Novel Angiotensin II Receptor Blocker Azilsartan Medoxomil Ameliorates Insulin Resistance Induced by Chronic Angiotensin II Treatment in Rat Skeletal Muscle. |
| 1108 | 23922555 | Angiotensin receptor (type 1) blockers (ARBs) can reduce both hypertension and insulin resistance induced by local and systemic activation of the renin-angiotensin-aldosterone system. |
| 1109 | 23922555 | The effectiveness of azilsartan medoxomil (AZIL-M), a novel imidazole-based ARB, to facilitate metabolic improvements in conditions of angiotensin II (Ang II)-associated insulin resistance is currently unknown. |
| 1110 | 23922555 | The aim of this study was to determine the impact of chronic AZIL-M treatment on glucose transport activity and key insulin signaling elements in red skeletal muscle of Ang II-treated rats. |
| 1111 | 23922555 | Furthermore, Ang II reduced insulin-mediated glucose transport activity in incubated soleus muscle, and AZIL-M co-treatment increased this parameter. |
| 1112 | 23922555 | Moreover, AZIL-M treatment of Ang II-infused animals increased the absolute phosphorylation of insulin signaling molecules, including Akt [both Ser473 (81%) and Thr308 (23%)] and AS160 Thr642 (42%), in red gastrocnemius muscle frozen in situ. |
| 1113 | 23922555 | Absolute AMPKα (Thr172) phosphorylation increased (98%) by AZIL-M treatment, and relative Thr389 phosphorylation of p70 S6K1, a negative regulator of insulin signaling, decreased (51%) with AZIL-M treatment. |
| 1114 | 23922555 | These results indicate that ARB AZIL-M improves the in vitro insulin action on glucose transport in red soleus muscle and the functionality of the Akt/AS160 axis in red gastrocnemius muscle in situ in Ang II-induced insulin-resistant rats, with the latter modification possibly associated with enhanced AMPKα and suppressed p70 S6K1 activation. |
| 1115 | 23994772 | Importantly, blockade of NADPH oxidase using apocynin diminished the induction of high Ang II stress markers in isolated cardiomyocytes and in the mouse heart. |
| 1116 | 23994772 | These effects were associated with inhibition of NADPH oxidase-mediated AKT/mTOR/S6K and ERK signaling pathways. |
| 1117 | 12975336 | Insulin and glucagon signaling in regulation of microsomal epoxide hydrolase expression in primary cultured rat hepatocytes. |
| 1118 | 12975336 | The phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin or LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one], and rapamycin, an inhibitor of p70 S6 kinase phosphorylation, ameliorated the insulin-mediated increase in mEH protein levels. |
| 1119 | 12975336 | The p38 mitogen-activated protein (MAP) kinase inhibitors SB203580 and SB202190 also abrogated the insulin-mediated increase in mEH protein. |
| 1120 | 12975336 | Furthermore, these data suggest that PI3K and p70 S6 kinase are active in the regulation of insulin-mediated mEH expression. |
| 1121 | 12975336 | We also provide data implicating p38 MAP kinase in the insulin-mediated increase in mEH levels. |
| 1122 | 12975336 | Insulin and glucagon signaling in regulation of microsomal epoxide hydrolase expression in primary cultured rat hepatocytes. |
| 1123 | 12975336 | The phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin or LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one], and rapamycin, an inhibitor of p70 S6 kinase phosphorylation, ameliorated the insulin-mediated increase in mEH protein levels. |
| 1124 | 12975336 | The p38 mitogen-activated protein (MAP) kinase inhibitors SB203580 and SB202190 also abrogated the insulin-mediated increase in mEH protein. |
| 1125 | 12975336 | Furthermore, these data suggest that PI3K and p70 S6 kinase are active in the regulation of insulin-mediated mEH expression. |
| 1126 | 12975336 | We also provide data implicating p38 MAP kinase in the insulin-mediated increase in mEH levels. |