Oncogenic Function of a P53-Induced Phosphatase

描述（由申请人提供）：肿瘤抑制因子p53在大多数人类肿瘤中在结构上或功能上失活。在那些保留完整p53的肿瘤中，p53信号通常通过改变其他分子的表达而失活。这种p53功能失活的一个例子发生在一部分人肉瘤中，其中致癌基因mdm2的扩增和过表达导致p53降解。最近的两篇文献报道暗示了另一种潜在的致癌基因可能会使人类乳腺癌和前列腺癌中的p53失活。该基因编码野生型p53诱导的磷酸酶wip1或Ppm1 d)，在16%的人类乳腺癌中被扩增和过表达。它是在这些乳腺癌中唯一持续扩增的基因，在体外转化试验中显示转化活性。Wipl是由p53在电离或紫外线照射后诱导的，它已被证明可以使p38 MAP激酶去磷酸化，使其失活，并通过磷酸化抑制p38对p53的激活。据推测，Wipl是p53初始激活后间接抑制p53功能的负调控反馈回路的一部分。因此，人类肿瘤中Wipl的扩增可引起p53信号的抑制增强，并通过p53依赖机制促进肿瘤发生。该提案的一个主要目标是使用体外培养系统和动物模型（包括我们实验室产生的Wipl敲除小鼠）来测试多种情况下Wip1的致癌性。我们将确定Wipl的缺失是否通过增加p53活性赋予肿瘤抗性表型。我们还将研究Wipl在促进转化或肿瘤发生方面是否具有p53独立的作用，以及Wipl的哪些结构域对转化相关作用至关重要。本提案的第二个主要目标是确定受Wipl影响的正常细胞信号通路，试图了解该磷酸酶的正常生物学功能。将鉴定wip1相互作用蛋白，并探索它们与Wipl的关系。我们的总体目标是更好地理解这种假定的人类致癌基因影响正常和致癌细胞信号传导的分子机制。

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.