PDGF inactivates forkhead family transcription factor by activation of Akt in glomerular mesangial cells

Cell Signal. 2003 Feb;15(2):161-70. doi: 10.1016/s0898-6568(02)00057-8.

Abstract

Regulation of the forkhead domain transcription factors by PDGF has not been studied. In this report, we investigated the role of PDGF-induced Akt in regulating forkhead domain protein FKHRL1 in glomerular mesangial cells. PDGF increased phosphorylation of FKHRL1 in a time- and PI 3 kinase-dependent manner. Expression of dominant negative Akt by adenovirus-mediated gene transfer blocked PDGF-induced FKHRL1 phosphorylation. PDGF inhibited transcription of a forkhead DNA binding element-driven reporter gene. This inhibition was mimicked by constitutively active myristoylated Akt. Moreover, FKHR1-mediated transcription of the reporter gene was completely attenuated by both PDGF and Myr-Akt. One of the targets of forkhead transcription factors is the proapoptotic Fas ligand (FasL) gene. PDGF, as well as Myr-Akt, inhibited transcription of FasL. In contrast, inhibition of PI 3 kinase and dominant negative Akt increased FasL gene transcription, suggesting that suppression of PI 3 kinase/Akt signalling may induce apoptosis in mesangial cells via upregulation of FasL expression. However, expression of dominant negative Akt by adenovirus did not induce apoptosis in mesangial cells, suggesting that Akt-independent antiapoptotic mechanisms also exist. Together, our data demonstrate for the first time that PDGF inactivates forkhead domain transcription factor by Akt-dependent phosphorylation and that suppression of Akt signalling is not sufficient to induce apoptosis in mesangial cells.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Fas Ligand Protein
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Gene Expression / drug effects
  • Genes, Reporter
  • Glomerular Mesangium / cytology
  • Glomerular Mesangium / metabolism*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Nerve Tissue Proteins
  • Phosphorylation / drug effects
  • Platelet-Derived Growth Factor / pharmacology*
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic / drug effects

Substances

  • DNA-Binding Proteins
  • FOXO3 protein, rat
  • Fas Ligand Protein
  • Faslg protein, rat
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Membrane Glycoproteins
  • Nerve Tissue Proteins
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Foxo1 protein, rat
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt