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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Blotting, Northern
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Blotting, Western
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Cell Line
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Chromatin / chemistry
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Chromatin / metabolism
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Cyclin D1 / metabolism
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Electrophoretic Mobility Shift Assay
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Fibroblasts / physiology
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Gene Expression Regulation
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Genes, Tumor Suppressor / physiology*
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Glutathione Transferase / metabolism
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Humans
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Immunoblotting
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Mice
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Mice, Knockout
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Nuclear Proteins*
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PTEN Phosphohydrolase
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Phosphoric Monoester Hydrolases / metabolism*
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Phosphoric Monoester Hydrolases / physiology*
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Precipitin Tests
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-mdm2
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Transfection
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Tumor Suppressor Protein p53 / genetics*
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins / physiology*
Substances
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Chromatin
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Nuclear Proteins
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Proto-Oncogene Proteins
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Cyclin D1
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MDM2 protein, human
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Mdm2 protein, mouse
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Proto-Oncogene Proteins c-mdm2
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Glutathione Transferase
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase
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PTEN protein, human