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: 6608854
• 负责人: Luis A. Martinez
• 金额: $ 9.57万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 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 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6608854
• 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 首席研究人员要发展独立的研究职业 专注于p53在前列腺癌中的作用。 接受的培训 奖项期间的候选人将桥接从 对独立研究人员的指导科学家。 候选人将从 细胞周期调节和前列腺研究的先前研究经验 癌症的病因来实现他的目标。 共同发起人，博士。 Nora M. Navone和Guillermina Lozano将提供出色的培训体验 对于U.T.M.D.最先进的机构设施的候选人 德克萨斯州休斯顿的安德森。 该提议的推动力是发现 到50％的转移性前列腺癌具有突变的p53。 鉴于 人类癌症中p53失活的高发病率，据推测 未证明p53突变的癌症必须具有上游或 下游改变，可以消除p53基因突变的需求。 尽管通过许多组对p53的细胞周期蛋白/CDK调节进行了分析，但 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 通过前列腺癌细胞中的磷酸化。 而且，我们已经生成了 可检验的假设，生长因子受体途径可以失活 P53通过细胞周期蛋白/CDK。 该建议旨在阐明替代方案 调节p53功能的机制。 这个特定的目的 提案如下：1）确定p53对p53的不稳定 细胞周期蛋白/CDK； 2）通过生长因子受体阐明p53的调节 通过细胞周期蛋白/CDK的途径； 3）确定抑制细胞周期蛋白/CDK是否 活动与雄激素消融协同作用以促进p53依赖性肿瘤 抑制。 该提案的目的将使用多种 包括共转染实验的方法，蛋白质印迹分析， 腺病毒介导的基因递送，定位诱变，体内（小鼠） 研究和其他与拟议研究生涯一致的方法 候选人的计划。 该提案中概述的研究将提供 消除新型治疗方法的基础 前列腺癌。