The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway

Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15587-91. doi: 10.1073/pnas.95.26.15587.

Abstract

The PTEN/MMAC1 phosphatase is a tumor suppressor gene implicated in a wide range of human cancers. Here we provide biochemical and functional evidence that PTEN/MMAC1 acts a negative regulator of the phosphoinositide 3-kinase (PI3-kinase)/Akt pathway. PTEN/MMAC1 impairs activation of endogenous Akt in cells and inhibits phosphorylation of 4E-BP1, a downstream target of the PI3-kinase/Akt pathway involved in protein translation, whereas a catalytically inactive, dominant negative PTEN/MMAC1 mutant enhances 4E-BP1 phosphorylation. In addition, PTEN/MMAC1 represses gene expression in a manner that is rescued by Akt but not PI3-kinase. Finally, higher levels of Akt activation are observed in human prostate cancer cell lines and xenografts lacking PTEN/MMAC1 expression when compared with PTEN/MMAC1-positive prostate tumors or normal prostate tissue. Because constitutive activation of either PI3-kinase or Akt is known to induce cellular transformation, an increase in the activation of this pathway caused by mutations in PTEN/MMAC1 provides a potential mechanism for its tumor suppressor function.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor*
  • Humans
  • Male
  • Mice
  • Mice, SCID
  • PTEN Phosphohydrolase
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoric Monoester Hydrolases / metabolism*
  • Polymerase Chain Reaction
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Transfection
  • Transplantation, Heterologous
  • Tumor Suppressor Proteins*

Substances

  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Tumor Suppressor Proteins
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human