Roles and Regulation of p53

描述(申请人提供)：这个项目的目标是使用跨学科和协作的方法，通过生物化学、基于细胞的分析、小鼠模型、信息学和人类肿瘤的分析来阐明P53和相关蛋白在肿瘤发生中的作用和调节。Carol Prives将研究检查点激酶1和2对P53家族的调控，将描述P53家族成员与新发现的蛋白质以及彼此之间的相互作用，并将确定不同的家族成员如何在DMA中受到调控并与其靶基因相互作用。Arnold Levine将识别和表征在细胞中组成p53途径的基因中发现的单核苷酸多态(SNP)，并将利用先前设计的算法在小鼠和人类基因组中识别新的p53靶基因。斯科特·洛将使用EP。-myc转基因模型，以确定通过PI3K/Akt通路的生存信号如何促进体内的化疗耐药，以及参与细胞凋亡、衰老和生存信号的基因如何影响p53的作用和治疗结果。他还将利用RNAi文库的可用性来识别在这个模型中影响化疗结果的新基因。Carlos Cordon-Cardo将评估人类患者膀胱癌中P53途径、P53 DNA损伤反应和PTEN/AKT途径变化的预测意义。这些不同的首席调查员之间规划了多个合作项目，这些项目不是任何一个调查员能够完成的。因此，该计划将利用四名研究人员的个人和联合专业知识，他们正在使用互补的方法来开发癌症治疗和诊断的翻译方法。

DESCRIPTION (provided by applicant): The goals of this program are to use an interdisciplinary and collaborative approach to elucidate the roles and regulation of p53 and related proteins in tumorigenesis using biochemistry, cell based assays, mouse models, informatics and analysis of human tumors. Carol Prives will study the regulation of the p53 family by the checkpoint kinases 1 and 2, will characterize the interactions of p53 family members with newly identified proteins and with each other and will determine how different family members are regulated and interact with their target genes in DMA. Arnold Levine will identify and characterize the single nucleotide polymorphisms (SNP's) that are found in the genes which compose the p53 pathway in cells, and will utilize a previously designed algorithm to identify novel p53 target genes in the mouse and human genome. Scott Lowe will use the Ep. -myc transgenic model to determine how survival signaling through the PI3K/Akt pathway promotes chemoresistance in vivo, and how genes involved in apoptosis, senescence, and survival signaling influence p53 action and treatment outcome. He will also utilize the availability of RNAi libraries to identify new genes that influence chemotherapy outcome in this model. Carlos Cordon-Cardo will evaluate the predictive significance of alterations in the p53 pathway, p53 DNA damage response and the PTEN/AKT pathway in bladder cancers from human patients. Multiple collaborative projects between these different Principal Investigator's are planned that cannot be accomplished by any single investigator. This program will thus exploit the individual and combined expertise of four researchers who are using complementary approaches to develop a translational approach for treatment and diagnosis of cancer.