Cyclin/cdk Regulation of P53 in Prostate Cancer

前列腺癌中 P53 的细胞周期蛋白/cdk 调节

• 批准号: 6909063
• 负责人: Luis A. Martinez
• 金额: $ 9.99万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6909063
• 关键词: Adenoviridae; androgen receptor; androgens; antineoplastics; antitumor antibody; athymic mouse; cell line; combination cancer therapy; cyclin dependent kinase; cyclins; enzyme activity; enzyme inhibitors; epidermal growth factor; gene induction /repression; growth factor receptors; hormone regulation /control mechanism; laboratory mouse; male castration; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; p53 gene /protein; prostate neoplasms; site directed mutagenesis

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.

描述（由申请人提供）：该提案的长期目标是 为首席研究员发展独立的研究生涯 重点关注 p53 在前列腺癌中的作用。 所接受的培训 获奖期间的候选人将在从 指导科学家成为独立研究员。 候选人将从 先前在细胞周期调控和前列腺研究方面的研究经验 癌症病因学来实现他的目标。 共同发起人，博士。诺拉·M. Navone 和 Guillermina Lozano 将提供出色的训练体验 为候选人提供 U.T.M.D. 最先进的机构设施 安德森，休斯敦，德克萨斯州。 这项提案的推动力是发现 50% 的转移性前列腺癌有 p53 突变。 鉴于 p53 失活在人类癌症中发生率很高，推测 未表现出 p53 突变的癌症必须具有上游或 下游改变消除了 p53 基因突变的需要。 尽管许多组对细胞周期蛋白/cdk 对 p53 的调节进行了分析，但没有发现 存在共识。 我们的假设是细胞周期蛋白/cdk 复合物破坏 p53 的稳定性 通过前列腺癌细胞中的磷酸化。 此外，我们还生成了 生长因子受体途径可以失活的可检验假设 p53 通过细胞周期蛋白/cdks。 该提案旨在阐明替代方案 p53 功能的调节机制。 本次活动的具体目标 建议如下： 1) 通过以下方式确定 p53 的不稳定 细胞周期蛋白/cdks； 2) 阐明生长因子受体对p53的调节 通过细胞周期蛋白/cdks 的途径； 3) 判断是否抑制cyclin/cdk 活性与雄激素消融协同促进 p53 依赖性肿瘤 抑制。 该提案的目标将通过多种方式来实现 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，定点诱变，体内（小鼠） 研究以及与拟议研究职业一致的其他方法 候选人的计划。 本提案中概述的研究将提供 产生新的治疗方法以消除的基础 前列腺癌。