Transcriptional regulation of insulin receptor substrate 1 by protein kinase C.
Insulin receptor substrate-1 (IRS-1) is involved in insulin signal transduction distal to receptor occupation. Targeted disruption of IRS-1 leads to insulin resistance and hyperglycemia in mice, which suggests that altered IRS-1 expression could contribute to the insulin resistance seen in non-insulin-dependent diabetes mellitus. In vitro studies using phorbol esters have implicated the protein kinase C (PKC) pathway as being involved in the pathogenesis of insulin resistance. Using the MCF-7 breast cancer cell, a role for PKC in regulating IRS-1 expression was examined. In an MCF-7 cell line (MCF-7-PKC-alpha) that exhibits multiple alterations in PKC isoform expression, IRS-1 content was reduced to negligible levels relative to parental MCF-7 cells. This decrease in IRS-1 content was associated with a 30-fold reduction in IRS-1 transcription. In parental MCF-7 cells, PKC inhibitors (GF109203X (bisindolylmaleimide I) and staurosporine) reduced IRS-1 content. Chronic exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA; >8 h) reduced IRS-1 content and down-regulated the novel PKC-delta isoform. Bryostatin 1 inhibited TPA-induced depletion of both IRS-1 and PKC-delta expression in MCF-7 cells. Associated with TPA-induced reduction in IRS-1 content was a reduction in IRS-1 transcription. These data demonstrate that PKC can modulate IRS-1 content and suggest a potential role for PKC-delta in positively regulating IRS-1 expression.
deVente
J E
JE
Department of Medicine, East Carolina University School of Medicine, Greenville, North Carolina 27858, USA.
Carey
J O
JO
Bryant
W O
WO
Pettit
G J
GJ
Ways
D K
DK
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D054713:Bryostatins; D015536:Down-Regulation; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D007527:Isoenzymes / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology; D018942:Macrolides; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D054713:Bryostatins; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D007527:Isoenzymes; D007783:Lactones; D018942:Macrolides; D010750:Phosphoproteins; C046785:bryostatin 1; C497259:Prkcd protein, mouse; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D013755:Tetradecanoylphorbol Acetate