title: PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA 90095, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Freeman
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Li
authors.forename: Gang
authors.initials: G
authors.lastname: Wei
authors.forename: Heng-Hong
authors.initials: HH
authors.lastname: Li
authors.forename: Nathalie
authors.initials: N
authors.lastname: Kertesz
authors.forename: Ralf
authors.initials: R
authors.lastname: Lesche
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Whale
authors.forename: Hilda
authors.initials: H
authors.lastname: Martinez-Diaz
authors.forename: Nora
authors.initials: N
authors.lastname: Rozengurt
authors.forename: Robert D
authors.initials: RD
authors.lastname: Cardiff
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005347:Fibroblasts / Q000502:physiology; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism* / Q000502:physiology*; D011233:Precipitin Tests; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D002843:Chromatin; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D005982:Glutathione Transferase; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human