P53-Mediated G1/M Checkpoint Controls Altered by PPM1D

PPM1D改变P53介导的Gl/M检查点调控 P53肿瘤抑制蛋白是一种序列特异性转录因子，调节细胞对 基因毒性应激和其他形式的细胞应激。PPM1D(正式名称为WIPL)在转录上被激活 以P53依赖的方式对基因毒性应激做出反应。它编码一种针对应激诱导的蛋白质磷酸酶 P38MAPK，它破坏了p38MAPK-P53信号通路。这与心脏的变化有关 P53蛋白N末端的磷酸化模式。N-末端磷酸化是P53蛋白表达的重要途径 起到转录因子的作用。我们和其他人已经证明，强迫外源表达PPM ID会减弱 对DNA损伤剂的细胞凋亡反应。降低人体肿瘤细胞中的PPM1D 表达它是由于基因扩增增强了对化疗药物的凋亡反应。这与以下内容相关 促凋亡基因Bax表达水平的变化。本项目的目标是阐明 以及PPM1D在调节p53转录活性中所起的作用。 PPM1D阻断p38MAPK-P53信号通路影响P53介导的反应基因转录 参与细胞周期检查点控制和/或细胞凋亡。具体目标如下：1)确定是否 PPM ID介导的p38MAPK-P53信号中断改变P53蛋白与P53反应之间的相互作用 下游靶基因的元件。2)确定PPMID是否介导了p38MAPK-P53信号的中断 改变P53蛋白与转录共激活因子的相互作用。3)鉴定和鉴定其基因 PPM ID介导的p38MAPK-p53信号通路的破坏改变了p38MAPK-P53的表达。 摘要：PPM1D是P53网络中的一个新成员，目前我们对其知之甚少。PPM1D 在含有野生型p53基因的人乳腺、卵巢和神经母细胞瘤中，基因经常被扩增。这 项目将提供有关PPM1D在细胞周期涉及的P53网络中所起作用的新信息 控制和细胞凋亡，并阐明这一作用的机制基础。

P53-Mediated Gl/M Checkpoint Controls Altered by PPM1D The p53 tumor suppressor protein is a sequence-specific transcription factor that modulates the response of cells to genotoxic stress and other forms of cellular stress. PPM1D (formally called Wipl) is transcriptionally-activated in response to genotoxic stress in a p53-dependent manner. It encodes a protein phosphatase that targets the stress induced kinase p38MAPK which disrupts the p38MAPK-p53 signalingpathway. This is correlated with alterations in the pattern of N-terminal phosphorylation on p53 protein. N-terminal phosphorylation is important for p53 protein to function as a trariscriptional factor. We and others have shown that forced exogenous expression of PPM ID attenuates the apoptotic response to DNA-damaging agents. Decreasing PPM1D in human tumor cells that constitutively over express it due to gene amplification enhances the apoptotic response to chemotherapeutic agents. This is correlated with changes,in the level of expression of the pro-apoptotic Bax gene.The goal of this project is to elucidate the mechanistic basis and the role that PPM1D plays in modulatingthe transcriptional activity of p53.The hypothesis to be tested is that disruption of the p38MAPK-p53 signaling pathway by PPM1D affects p53-mediated transcription of responsive genes involved in cell cycle checkpoint control and/or apoptosis. The Specific Aims are the following: 1) To determine if PPM ID-mediated disruptionof p38MAPK-p53 signalingalters the interaction between p53 protein and p53-responsive elements of downstream target genes. 2) To determine if PPMID-mediated disruptionof p38MAPK-p53 signaling alters the interaction of p53 protein with transcriptional coactivators. 3) To identify and characterize genes whose expression is altered by PPM ID-mediated disruption of the p38MAPK-p53 signaling pathway. Lay Abstract: PPM1D is a new player in the p53 network about which we know very little at present. The PPM1D gene is often amplified in human breast, ovarian and neuroblastoma tumors that harbor a wild type p53 gene. This project will provide new informationregarding the role that PPM1D plays in the p53 network involved in cell cycle control and apopotosis and elucidate the mechanistic basis for this action.