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PTEN regulates Mdm2 expression through the P1 promoter


, : PTEN regulates Mdm2 expression through the P1 promoter. Journal of Biological Chemistry 279(28): 29841-8

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 p90MDM2 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.

US$19.90

PMID: 15090541

DOI: 10.1074/jbc.M401488200


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