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 为主要研究者发展独立的研究生涯 p53在前列腺癌中的作用 接受之培训 在获奖期间，候选人将过渡到 从科学家到独立研究员 候选人将从 在细胞周期调节和前列腺研究方面的先前研究经验 癌症病因学来实现他的目标。 共同发起人诺拉·M. Navone和Guillermina Lozano将提供出色的培训体验 为候选人提供最先进的医疗设施 安德森，休斯顿，德克萨斯州。 这项提议的动力是发现， 到50%的转移性前列腺癌有突变的p53。 鉴于 p53失活在人类癌症中的高发生率，推测 未显示p53突变的癌症必须具有上游或下游突变， 下游改变，从而避免了对p53基因突变的需要。 尽管许多研究小组分析了cyclin/cdk对p53的调节，但没有发现p53的表达与cyclin/cdk的表达有关。 有共识。 我们的假设是cyclin/cdk复合物使p53不稳定 通过前列腺癌细胞中的磷酸化。 此外，我们还产生了 生长因子受体途径可以抑制 p53通过cyclin/cdks表达。 本建议旨在阐明替代方案 调节p53功能的机制。 具体目标是 提案 如下：1）通过以下测定p53的不稳定： 2）阐明生长因子受体对p53的调控作用 3）确定细胞周期蛋白/cdk的抑制是否 活性与雄激素消除协同促进p53依赖性肿瘤 镇压 本提案的目的将通过各种 包括共转染实验，蛋白质印迹分析， 腺病毒介导的基因递送，定点诱变，体内（小鼠） 研究，以及与拟议的研究生涯相一致的其他方法 候选人的计划。 本提案中概述的研究将提供 产生新的治疗方法的基础，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.