Oncogenic Function of a P53-Induced Phosphatase

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DESCRIPTION (provided by applicant): The tumor suppressor p53 is structurally or functionally inactivated in most human tumors. In those tumors that retain intact p53, p53 signaling is often inactivated through altered expression of other molecules. An example of this p53 functional inactivation occurs in a fraction of human sarcomas, in which amplification and overexpression of the oncogene mdm2 results in p53 degradation. Two recent reports in the literature implicate another potential oncogene that may inactivate p53 in human breast and prostate cancers. This gene, encoding the wildtype p53-induced phosphatase wip1 or Ppm1 d). is amplified and overexpressed in 16% of human breast cancers. It is the only consistently amplified gene in these breast cancers that shows transforming activity in in vitro transformation assays. Wipl is induced by p53 following ionizing or ultraviolet radiation and it has been shown to dephosphorylate p38 MAP kinase, inactivating it and inhibiting p38 activation of p53 through phosphorylation. It is hypothesized that Wipl forms part of a negative regulatory feedback loop that indirectly inhibits p53 function following initial activation of p53. Thus, amplification of Wipl in human tumors could cause increased inhibition of p53 signaling and promote tumorigenesis through p53-dependent mechanisms. A major goal of this proposal is to use in vitro culture systems and animal models (including a Wipl knockout mouse that our laboratory has generated) to test the oncogenicib, of Wip1 in multiple contexts. We will determine whether the absence of Wipl confers a tumor resistance phenotype through increased p53 activity. We will also examine whether Wipl has p53-independent effects in enhancement of transformation or tumorigenesis and which domains of Wipl are crucial for transformation-related effects. A second major goal of this proposal is to identify normal cell signaling pathways influenced by Wipl in an attempt to understand the normal biological functions of this phosphatase. Wip1-interacting proteins will be identified and their relationship to Wipl will be explored. Our overall goal is to better understand the molecular mechanisms by which this putative human oncogene affects both normal and oncogenic cell signaling.