PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms

Cancer Cell. 2003 Feb;3(2):117-30. doi: 10.1016/s1535-6108(03)00021-7.


We show in this study that PTEN regulates p53 protein levels and transcriptional activity through both phosphatase-dependent and -independent mechanisms. The onset of tumor development in p53(+/-);Pten(+/-) mice is similar to p53(-/-) animals, and p53 protein levels are dramatically reduced in Pten(-/-) cells and tissues. Reintroducing wild-type or phosphatase-dead PTEN mutants leads to a significant increase in p53 stability. PTEN also physically associates with endogenous p53. Finally, PTEN regulates the transcriptional activity of p53 by modulating its DNA binding activity. This study provides a novel mechanism by which the loss of PTEN can functionally control "two" hits in the course of tumor development by concurrently modulating p53 activity.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Northern
  • Blotting, Western
  • Cell Line
  • Chromatin / chemistry
  • Chromatin / metabolism
  • Cyclin D1 / metabolism
  • Electrophoretic Mobility Shift Assay
  • Fibroblasts / physiology
  • Gene Expression Regulation
  • Genes, Tumor Suppressor / physiology*
  • Glutathione Transferase / metabolism
  • Humans
  • Immunoblotting
  • Mice
  • Mice, Knockout
  • Nuclear Proteins*
  • PTEN Phosphohydrolase
  • Phosphoric Monoester Hydrolases / metabolism*
  • Phosphoric Monoester Hydrolases / physiology*
  • Precipitin Tests
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-mdm2
  • Transfection
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / physiology*


  • Chromatin
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Cyclin D1
  • MDM2 protein, human
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2
  • Glutathione Transferase
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human