Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor

Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7200-5. doi: 10.1073/pnas.121173298. Epub 2001 Jun 12.

Abstract

Whereas several apoptosis-related proteins have been linked to the antiapoptotic effects of Akt serine-threonine kinase, the search continues to explain the Akt signaling role in promoting cell survival via antiapoptotic effects. Here, we demonstrate that Akt phosphorylates the androgen receptor (AR) at Ser-210 and Ser-790. A mutation at AR Ser-210 results in the reversal of Akt-mediated suppression of AR transactivation. Activation of the phosphatidylinositol-3-OH kinase/Akt pathway results in the suppression of AR target genes, such as p21, and the decrease of androgen/AR-mediated apoptosis, which may involve the inhibition of interaction between AR and AR coregulators. Together, these findings provide a molecular basis for cross-talk between two signaling pathways at the level of Akt and AR-AR coregulators that may help us to better understand the roles of Akt in the androgen/AR-mediated apoptosis.

Publication types

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

MeSH terms

  • Amino Acid Substitution
  • Androgen Receptor Antagonists
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Chromones / pharmacology
  • Dihydrotestosterone / pharmacology*
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Male
  • Morpholines / pharmacology
  • Mutagenesis, Site-Directed
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Prostatic Neoplasms
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Receptors, Androgen / genetics
  • Receptors, Androgen / physiology*
  • Recombinant Proteins / metabolism
  • Serine
  • Signal Transduction
  • Transcriptional Activation* / drug effects
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Androgen Receptor Antagonists
  • Chromones
  • Enzyme Inhibitors
  • Morpholines
  • Proto-Oncogene Proteins
  • Receptors, Androgen
  • Recombinant Proteins
  • Dihydrotestosterone
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Serine
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt