Abstract
MDM2 is an oncoprotein that controls tumorigenesis through both p53-dependent and -independent mechanisms. Mdm2 mRNA level is transcriptionally regulated by p53 in response to stress such as DNA damage, and its protein level and subcellular localization are post-translationally modulated by the AKT serine/threonine kinase. Previous studies showed that PTEN, a dual specificity phosphatase that antagonizes phosphatidylinositol 3-kinase/AKT signaling, is capable of blocking MDM2 nuclear translocation and destabilizing the MDM2 protein. Results from our current study demonstrate an additional role for PTEN in regulating MDM2 functions; PTEN modulates Mdm2 transcription and isoform selection by negatively regulating its P1 promoter. In Pten-null cell lines and prostate cancer tissues, Mdm2 P1 promoter activity is up-regulated, resulting in increased L-Mdm2 expression and enhanced p90(MDM2) isoform production. Furthermore, PTEN controls Mdm2 P1 promoter activity through its lipid phosphatase activity, independent of p53. Thus, our results provide a novel mechanism for PTEN in controlling MDM2 oncoprotein functions.
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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Cells, Cultured
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Fibroblasts / cytology
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Fibroblasts / physiology
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Gene Expression Regulation*
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Humans
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Male
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Mice
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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PTEN Phosphohydrolase
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Promoter Regions, Genetic*
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Prostate / metabolism
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-mdm2
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RNA, Messenger / metabolism
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Signal Transduction / physiology
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Transcription, Genetic
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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Nuclear Proteins
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Protein Isoforms
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Proto-Oncogene Proteins
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RNA, Messenger
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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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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Protein Tyrosine Phosphatases
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PTEN Phosphohydrolase
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Pten protein, mouse