Activation of protein kinase B/Akt is sufficient to repress the glucocorticoid and cAMP induction of phosphoenolpyruvate carboxykinase gene

J Biol Chem. 1998 Oct 16;273(42):27320-4. doi: 10.1074/jbc.273.42.27320.

Abstract

A rat hepatoma cell line, H4IIE, was stably transfected with a tamoxifen regulatable Akt-1 construct. Treatment of these cells with tamoxifen caused a rapid stimulation of Akt enzymatic activity that was comparable with the activity observed with the endogenous Akt after insulin stimulation. Prior studies have extensively documented that insulin can repress the glucocorticoid and cAMP-stimulated increase in phosphoenolpyruvate carboxykinase (PEPCK) gene transcription. Activation of this regulatable Akt with tamoxifen was found to mimic the dominant inhibitory effect of insulin on PEPCK gene transcription. Dose response curves to insulin and tamoxifen demonstrated that this response was very sensitive to Akt activation although the maximal response observed with tamoxifen activation was slightly less than that observed with insulin, indicating that the response to insulin may also involve other signaling cascades. The regulation of PEPCK transcription via Akt was, like that previously described for insulin, not dependent upon 70 kDa S6 kinase activity in that it was not inhibited by rapamycin. Finally, the expression of a kinase dead Akt was able to partially inhibit the ability of insulin to stimulate this response. In summary, the present results indicate that activation of Akt alone is sufficient to repress the glucocorticoid and cAMP-stimulated increase in PEPCK gene transcription.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Chromones / pharmacology
  • Cyclic AMP / pharmacology*
  • Dexamethasone / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Activation
  • Enzyme Repression
  • Glucocorticoids / pharmacology
  • Gluconeogenesis
  • Insulin / pharmacology*
  • Liver / cytology
  • Morpholines / pharmacology
  • Phosphoenolpyruvate Carboxykinase (ATP) / biosynthesis*
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Ribosomal Protein S6 Kinases / antagonists & inhibitors
  • Sirolimus / pharmacology
  • Tamoxifen / pharmacology
  • Transcription, Genetic / drug effects

Substances

  • Chromones
  • Glucocorticoids
  • Insulin
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Tamoxifen
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Dexamethasone
  • Cyclic AMP
  • Akt1 protein, rat
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases
  • Phosphoenolpyruvate Carboxykinase (ATP)
  • Sirolimus