The Role of Phosphatase CL100/MKP1 in Human Cancer

描述（由申请人提供）：CL 100/MKP 1是双特异性蛋白磷酸酶家族的成员，能够使丝裂原活化蛋白（MAP）激酶上的苏氨酸和酪氨酸残基脱磷酸化，因此在负调节MAP激酶活性中起关键作用。CL 100/MKP 1还能抑制DNA损伤诱导的细胞凋亡。CL 100/MKP 1是由多种刺激诱导的，包括氧化应激和生长因子。我们发现CLt 00 tMKP 1是p53的转录靶点。CL 100/MKP 1的调节机制，包括p53的作用及其与人类癌症的关系仍有待确定。我们的长期目标是了解癌细胞中信号转导途径的机制及其在化疗药物敏感性中的作用。本申请的目的是研究磷酸酶CL 100/MKP 1在人类癌症中p53介导的细胞应答中的作用。细胞暴露于氧化应激导致p53的活化、CL 100/MKP 1的诱导和MJ_P激酶的活化。这些考虑表明p53、CL 100/MKP 1和MAP激酶之间存在潜在联系。了解这些联系将有助于深入了解信号转导途径如何相互作用。我们的建议的新方面是p53通路和MAPK通路之间的潜在串扰。中心假设是双重磷酸酶CL 100/MKP 1是连接p53通路与MA、PK通路的介体。我们的假设是基于我们实验室的初步数据，表明CL 100 tMKP 1以p53依赖的方式上调。该申请的基本原理是，一旦p53介导的CL 100 iMKP 1调节机制已知，该过程的调节可能导致癌症治疗新策略的开发。我们将通过追求以下三个具体目标来测试我们的假设并实现本申请的目的：（1）确定p53对CL 100/MKP 1的调节;（2）确定CL 100/MKP 1在p53介导的细胞周期调节中的作用;以及（3）阐明CL 100/MKP 1在p53介导的细胞凋亡和化学敏感性中的作用。总的来说，我们的研究将为CL 100/MKP 1在人类癌症细胞周期和凋亡控制中的作用提供重要和新颖的见解。

DESCRIPTION (provided by applicant): CL100/MKP1 is a member of the dual specificity protein phosphatase family that is able to dephosphorylate both the threonine and tyrosine residues on mitogen-activated protein (MAP) kinases, and thus plays a critical role in negatively regulating the activises of MAP kinases. CL100/MKP1 can also inhibit DNA damage-induced apoptosis. CL100/MKP1 is induced by a variety of stimuli including oxidative stress and growth factors. We have made the novel observation that CLt00tMKP1 is a transcriptional target of p53. The mechanism by which CL100/MKP1 is regulated, including the role of p53, and its relationship to human cancer remain to be determined. Our long-range goal is to understand the mechanisms of the signal transduction pathways in cancer cells and their role in chemosensitivity to chemotherapeutic drugs. The objective of this application is to study the role of the phosphatase CL100/MKP1 in p53-mediated cellular responses in human cancer. Exposure of cells to oxidative stress results in activation of p53, induction of CL100/MKP1, and activation of MJ_P kinases. These considerations suggest potential links among p53, CL100/MKP1, and MAP kinases. Understanding these links will provide insights into how the signal tranduction pathways interact. The novel aspect of our proposal is the potential cross talk between the p53 pathway and the MAPK pathway. The central hypothesis is that the dual phosphatase CL100/MKP1 is a mediator that links the p53 pathway to the MA,PK pathway. Our hypothesis is based on preliminary data produced in our laboratory showing that CL100tMKP1 is upregulated in a p53_ependent fashion. The rationale for the application is that, once the mechanism of p53-mediated regulation of CL100iMKP1 is known, modulation of this process may lead to the development of a novel strategy for cancer treatment. We will test our hypothesis and accomplish the objectives of this application by pursuing the following three specific aims: (1) Determine the regulation of CL100/MKP1 by p53; (2) Define the role of CL100fMKP1 in p53-mediated cell cycle regulation; and (3) Elucidate the role of CL100/MKP1 in p53-mediated apoptosis and chemosensitivity. Collectively, our studies will provide important and novel insights into the role of CL100/MKP1 in cell cycle and apoptosis control in human cancer.