Insulin Regulation of Glucose-6-phosphate Dehydrogenase Gene Expression Is Rapamycin-sensitive and Requires Phosphatidylinositol 3-Kinase
Glucose-6-phosphate dehydrogenase (G6PDH) controls the flow of carbon through the pentose phosphate pathway and also produces NADPH needed for maintenance of reduced glutathione and reductive biosynthesis. Hepatic expression of G6PDH is known to respond to several dietary and hormonal factors, but t...
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Veröffentlicht in: | The Journal of biological chemistry 1998-06, Vol.273 (24), p.14968-14974 |
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Zusammenfassung: | Glucose-6-phosphate dehydrogenase (G6PDH) controls the flow of carbon through the pentose phosphate pathway and also produces NADPH needed for maintenance of reduced glutathione and reductive biosynthesis. Hepatic expression of G6PDH is known to respond to several dietary and hormonal factors, but the mechanism behind regulation of this expression has not been characterized. We show that insulin similarly induces expression of endogenous hepatic G6PDH and a reporter construct containing 935 base pairs of the G6PDH promoter linked to luciferase in transient transfection assays. Using well tested and structurally distinct inhibitors of Ras farnesylation, lovastatin and B581, and a specific inhibitor of mitogen-activated protein kinase kinase activation, PD 98059, we show that the Ras/Raf/mitogen-activated protein kinase pathway is not utilized for the insulin-induced stimulation of G6PDH gene expression in primary rat hepatocytes. Similarly, using well characterized inhibitors of phosphatidylinositol 3-kinase, wortmannin and LY 294002, we show that PI 3-kinase activity is necessary for the induction of G6PDH expression by insulin. Rapamycin, an inhibitor of FRAP protein, which is involved in the activation of pp70 S6 kinase, blocks the insulin induction of G6PDH, suggesting that S6 kinase is also necessary for the insulin induction of G6PDH expression. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.273.24.14968 |