Cyclin/cdk Regulation of P53 in Prostate Cancer

描述(由申请人提供)：本提案的长期目标是 首席调查员要发展独立的研究事业 重点研究了P53在前列腺癌中的作用。该公司接受的培训 在获奖期间，候选人将从 从科学家到独立研究人员的导师。候选人将从 细胞周期调控与前列腺研究的经验 癌症病因学来完成他的目标。共同发起人，诺拉·M博士。 Navone和Guillermina Lozano将提供极好的训练体验 对于在德克萨斯大学医学院最先进的机构设施中的候选人。 安德森，德克萨斯州休斯顿这项提议的推动力是发现 到50%的转移性前列腺癌有突变的P53。给定 P53失活在人类癌症中的高发生率，据推测 没有表现出p53突变的癌症必须有上游或 下游改变，消除了对p53基因突变的需要。 尽管一些小组分析了细胞周期蛋白/cdk对p53的调控，但没有 存在共识。我们的假设是细胞周期蛋白/cdk复合体破坏了p53的稳定性。 通过前列腺癌细胞中的磷酸化。此外，我们还产生了 生长因子受体通路失活的可验证性假说 P53通过细胞周期蛋白/CDKs途径表达。这项提议旨在阐明替代方案 P53功能的调控机制。这样做的具体目的是 建议如下：1)通过以下方式确定P53的失稳 Cyclin/CDKs；2)阐明生长因子受体对P53的调控 Cyclin/CDK途径；3)决定是否抑制Cyclin/CDK 雄激素消融促进P53依赖性肿瘤的活性 压制。这项提案的目标将使用各种 方法包括共转染实验，蛋白质印迹分析， 腺病毒介导的基因传递，体内定点突变(小鼠) 与拟议的研究职业生涯相一致的研究和其他方法 候选人的计划。本提案中概述的研究将提供 产生新的治疗方法以消除 前列腺癌。

DESCRIPTION (provided by applicant): The long term goal of this proposal is for the principal investigator to develop an independent research career focused on the role of p53 in prostate cancer. The training received by the candidate during the period of the award will bridge the transition from mentored scientist to independent researcher. The candidate will draw from prior research experience in the study of cell cycle regulation and prostate cancer etiology to accomplish his objectives. The co-sponsors, Drs. Nora M. Navone and Guillermina Lozano will provide an excellent training experience for the candidate in the state-of-the-art institutional facilities at U.T.M.D. Anderson, Houston, TX. The impetus for this proposal is the finding that up to 50 percent of metastatic prostate cancers have a mutated p53. Given the high incidence of p53 inactivation in human cancers, it is presumed that cancers that do not demonstrate p53 mutation must have either an upstream or downstream alteration that obviates the need for mutation of the p53 gene. Despite the analysis of cyclin/cdk regulation of p53 by a number of groups, no consensus exists. Our hypothesis is that cyclin/cdk complexes destabilize p53 through phosphorylation in prostate cancer cells. Moreover, we have generated a testable hypothesis whereby growth factor receptor pathways can inactivate p53 via the cyclin/cdks. This proposal seeks to elucidate alternative mechanisms for the regulation of p53 function. The specific aims of this proposal are as follows: 1) Determine the destabilization of p53 by cyclin/cdks; 2) To elucidate the regulation of p53 by growth factor receptor pathways via cyclin/cdks; 3) Determine whether inhibition of cyclin/cdk activity synergizes with androgen ablation to promote p53 dependent tumor suppression. The aims of this proposal will be addressed using a variety of approaches including co-transfection experiments, western blot analysis, adenovirus-mediated gene delivery, site-directed mutagenesis, in vivo (mouse) studies, and other methodologies consistent with the proposed Research Career Plans of the candidate. The research outlined in this proposal will provide the basis for the generation of novel therapeutic approaches to eliminate prostate cancer.