Akt serine threonine kinase regulates platelet-derived growth factor-induced DNA synthesis in glomerular mesangial cells: Regulation of c-fos and p27kip1 gene expression

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Abstract

Proliferation of mesangial cells requires platelet-derived growth factor receptor β (PDGFR)-mediated signal transduction. We have previously shown that activation of phosphatidylinositol (PI) 3-kinase is necessary for PDGFR-induced DNA synthesis in these cells. The mechanism by which PI 3-kinase stimulates DNA synthesis is not known. One target of PI 3-kinase, Akt serine threonine kinase, regulates survival of many cells by inhibiting the actions of certain proapoptotic proteins. In this study, we investigated the role of Akt in PDGF-induced DNA synthesis in mesangial cells. PDGF increased Akt serine threonine kinase activity in a time- and PI 3-kinase-dependent manner. Expression of dominant negative Akt by adenovirus-mediated gene transfer blocked PDGF-induced activation of endogenous Akt in mesangial cells, resulting in complete inhibition of DNA synthesis. On the other hand, inhibition of MAPK attenuated PDGF-induced DNA synthesis only partially. Inhibition of Akt also attenuated PDGF-induced c-fos gene transcription, with concomitant inhibition of Elk-1-dependent transcription, indicating positive regulation of this early response gene by Akt. To further determine the role of Akt in PDGF-induced DNA synthesis, we investigated its effect on cyclin-dependent kinase 2 (CDK2). PDGF stimulated CDK2 activity in mesangial cells and decreased the level of p27 kip1 cyclin kinase inhibitor protein. Expression of dominant negative Akt increased p27kip1 protein and resulted in inhibition of CDK2 activity. The increase in p27kip1 expression in response to Akt kinase inhibition was due to increased transcription of the p27kip1 gene. p27kip1 transcription similarly was decreased by expression of constitutively active Akt kinase in mesangial cells. These data provide the first evidence that Akt kinase regulates PDGF-induced DNA synthesis by regulating CDK2 activity and define Akt-mediated inhibition of transcription of p27kip1 as one of the mechanisms for PDGF-induced DNA synthesis in mesangial cells.

Original languageEnglish (US)
Pages (from-to)35636-35643
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number38
DOIs
StatePublished - Sep 21 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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