Abstract
Insulin regulates the expression of multiple hepatic genes through a conserved insulin response sequence (IRS) (CAAAAC/TAA) by an as yet undetermined mechanism. Protein kinase B/Akt (PKB/Akt), a member of the PKA/PKC serine/threonine kinase family, functions downstream from phosphatidylinositol 3'-kinase (PI3K) in mediating effects of insulin on glucose transport and glycogen synthesis. We asked whether PKB/Akt mediates sequence-specific effects of insulin on hepatic gene expression using the model of the insulin-like growth factor binding protein-1 (IGFBP-1) promoter. Insulin lowers IGFBP-1 mRNA levels, inhibits IGFBP-1 promoter activity, and activates PKB/Akt in HepG2 hepatoma cells through a PI3K-dependent, rapamycin-insensitive mechanism. Constitutively active PI3K and PKB/Akt are each sufficient to mediate effects of insulin on the IGFBP-1 promoter in a nonadditive fashion. Dominant negative K179 PKB/Akt disrupts the ability of insulin and PI3K to activate PKB/Akt and to inhibit promoter activity. The IGFBP-1 promoter contains two IRSs each of which is sufficient to mediate sequence-specific effects of insulin, PI3K, and PKB/Akt on promoter activity. Highly related IRSs from the phosphoenolpyruvate carboxykinase and apolipoprotein CIII genes also are effective in this setting. These results indicate that PKB/Akt functions downstream from PI3K in mediating sequence-specific effects of insulin on the expression of IGFBP-1 and perhaps multiple hepatic genes through a conserved IRS.
Keywords
Protein kinase BInsulinInsulin receptorInsulin-like growth factorGRB10Internal medicineGeneEndocrinologyBiologyGrowth factorCell biologySignal transductionInsulin resistanceMedicineBiochemistryReceptor
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Publication Info
- Year
- 1998
- Type
- article
- Volume
- 273
- Issue
- 11
- Pages
- 6482-6487
- Citations
- 162
- Access
- Closed
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Cite This
Stephen B. Cichy,
Shahab Uddin,
Alexey Danilkovich
et al.
(1998).
Protein Kinase B/Akt Mediates Effects of Insulin on Hepatic Insulin-like Growth Factor-binding Protein-1 Gene Expression through a Conserved Insulin Response Sequence.
Journal of Biological Chemistry
, 273
(11)
, 6482-6487.
https://doi.org/10.1074/jbc.273.11.6482
Identifiers
- DOI
- 10.1074/jbc.273.11.6482