P53-Mediated G1/M Checkpoint Controls Altered by PPM1D

P53介导的Gl/M检查点控制被PPM 1D改变 p53肿瘤抑制蛋白是一种序列特异性转录因子，其调节细胞对以下的应答： 遗传毒性应激和其他形式的细胞应激。PPM 1D（正式名称为Wipl）是转录激活的， 以p53依赖的方式对遗传毒性应激的反应。它编码一种蛋白磷酸酶，靶向应激诱导的 激酶p38 MAPK，其破坏p38 MAPK-p53信号通路。这是与改变， p53蛋白N端磷酸化模式。N-末端磷酸化对于p53蛋白 作为一种制约因素。我们和其他人已经表明，PPM ID的强制外源表达减弱了 对DNA损伤剂的凋亡反应。降低人肿瘤细胞中的PPM 1D， 由于基因扩增而表达它增强了对化疗剂的凋亡反应。这与 促凋亡Bax基因表达水平的变化。本项目的目的是阐明促凋亡Bax基因表达水平的机制。 PPM 1D在调节p53转录活性中的作用。有待验证的假设是， PPM 1D对p38 MAPK-p53信号通路的破坏影响p53介导的应答基因转录 参与细胞周期检查点控制和/或凋亡。具体目标如下：1）确定是否 PPM ID介导的p38 MAPK-p53信号转导的破坏改变了p53蛋白和p53应答蛋白之间的相互作用 下游靶基因的元件。2)为了确定PPMID介导的p38 MAPK-p53信号转导的破坏是否 改变p53蛋白与转录辅激活因子的相互作用。3)为了识别和表征基因， 通过PPM ID介导的p38 MAPK-p53信号传导途径的破坏改变表达。 摘要：PPM 1D是p53网络中的一个新成员，目前我们对它知之甚少。PPM1D 在携带野生型p53基因的人乳腺癌、卵巢癌和神经母细胞瘤肿瘤中，p53基因经常被扩增。这 该项目将提供有关PPM 1D在参与细胞周期的p53网络中发挥作用的新信息 控制和凋亡，并阐明了这一行动的机制基础。

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.