The Role of Phosphatase CL100/MKP1 in Human Cancer

描述(申请人提供)：CL100/mkp1是双特异性蛋白磷酸酶家族的成员，它能够使丝裂原激活蛋白(MAP)激酶上的苏氨酸和酪氨酸残基去磷酸化，从而在负调控MAP激酶的活性中发挥关键作用。CL100/mkp1还可抑制DNA损伤诱导的细胞凋亡。CL100/mkp1受多种刺激诱导，包括氧化应激和生长因子。我们做了一个新的观察，CLt00tMKP1是P53的转录靶点。调节CL100/mkp1的机制，包括P53的作用，以及它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。这项应用的目的是研究磷酸酶CL100/MKP1在人类癌症中P53介导的细胞反应中的作用。细胞暴露于氧化应激可导致P53的激活、CL100/Mkp1的诱导和MJ_P激酶的激活。这些考虑提示了p53、CL100/mkp1和MAP激酶之间的潜在联系。了解这些联系将有助于深入了解信号转导通路是如何相互作用的。我们建议的新方面是P53通路和MAPK通路之间的潜在串扰。中心假设是双磷酸酶CL100/mkp1是连接P53途径和MA、PK途径的中介。我们的假设是基于我们实验室提供的初步数据，表明CL100tMKP1以P53依赖的方式上调。该应用的基本原理是，一旦知道了P53介导的CL100iMKP1的调节机制，对这一过程的调节可能会导致开发一种新的癌症治疗策略。我们将通过以下三个具体目标来验证我们的假设并实现这一应用的目标：(1)确定P53对CL100/mkp1的调节；(2)确定CL100fMKP1在P53介导的细胞周期调控中的作用；(3)阐明CL100/Mkp1在P53介导的细胞凋亡和化疗敏感性中的作用。总之，我们的研究将为CL100/mkp1在人类癌症细胞周期和凋亡控制中的作用提供重要的和新的见解。

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.