PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms.
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.
Freeman
Daniel J
DJ
Howard Hughes Medical Institute, Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA 90095, USA.
Li
Andrew G
AG
Wei
Gang
G
Li
Heng-Hong
HH
Kertesz
Nathalie
N
Lesche
Ralf
R
Whale
Andrew D
AD
Martinez-Diaz
Hilda
H
Rozengurt
Nora
N
Cardiff
Robert D
RD
Liu
Xuan
X
Wu
Hong
H
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*
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