Role of the Prolylisomerase Pin1 in Oncogenesis

Prolylisomerase Pin1 在肿瘤发生中的作用

• 批准号: 6688247
• 负责人: GERBURG M WULF
• 金额: $ 13.03万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-17 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6688247
• 关键词: antineoplastics; breast neoplasms; clinical research; disease /disorder model; enzyme inhibitors; female; gene expression; gene mutation; genetic transcription; genetically modified animals; guanine nucleotide binding protein; human tissue; laboratory mouse; natural gene amplification; neoplasm /cancer genetics; neoplastic process; peptidylprolyl isomerase; phosphorylation; protooncogene

DESCRIPTION (provided by applicant): Pin1 regulates the function of a subset of phosphoproteins, presumably by binding and isomerizing their phosphorylated S/T-P motifs (11-20). Inhibition of Pin1 causes growth arrest of tumor cells and contributes to neuronal death in Alzheimer's disease (11). I found that Pin1 is overexpressed in 75% of breast cancer specimens, and that it cooperates with Ras signaling in increasing c-Jun's transcriptional activity towards cyclin D1 (12). Pin1 also causes cyclin D1 accumulation by regulating the turnover and subcellular localization of beta-catenin (81). Loss of Pin1 function in knock-out mice mimics the cyclin D1 null phenotype and causes severe defects in mammary gland development (84). Given the crucial roles of Ras signaling and cyclin D1 in oncogenesis, our results suggest that overexpression of Pin1 may promote breast cancer growth. This proposal is to test this hypothesis with the following specific aims: (1) To examine the mechanism of overexpression of Pin1 in breast cancer a. examine whether overexpression of Pin1 is due to amplification or mutation. b. examine the transcriptional regulation of the Pin1 promoter. (2) To study the role of Pin1 in the transcription of specific genes a. define the role of Pin1 phosphorylation in its interaction with c-Jun b. analyze how Pin1 regulates c-jun stability and function. c. establish a profile of the genes that are specifically activated by Pin1. (3) To study the role of Pin1 in the development of cancer in vitro and in vivo a. analyze the transforming activity of Pin1 itself or in cooperation with Ras or ErbB2. b. analyze the significance of Pin1 for breast cancer development in a mouse model. (4) To study the effect of the inhibition of Pin1's PPIase activity as potential cancer therapy in vitro and in vivo. This project is designed to train the principal investigator for a career as an independent physician scientist.

描述（由申请人提供）：Pin1 可能通过结合和异构化磷酸化的 S/T-P 基序来调节磷蛋白子集的功能 (11-20)。 抑制 Pin1 会导致肿瘤细胞生长停滞，并导致阿尔茨海默病中的神经元死亡 (11)。 我发现 Pin1 在 75% 的乳腺癌样本中过度表达，并且它与 Ras 信号传导协同作用，增加 c-Jun 对细胞周期蛋白 D1 的转录活性 (12)。 Pin1 还通过调节 β-连环蛋白的周转和亚细胞定位来引起细胞周期蛋白 D1 积累 (81)。 基因敲除小鼠中 Pin1 功能的丧失模仿了细胞周期蛋白 D1 无效表型，并导致乳腺发育严重缺陷 (84)。 鉴于 Ras 信号传导和细胞周期蛋白 D1 在肿瘤发生中的关键作用，我们的结果表明 Pin1 的过度表达可能促进乳腺癌生长。 本提案旨在检验这一假设，具体目标如下： (1)探讨Pin1在乳腺癌中过度表达的机制 一个。检查 Pin1 的过度表达是否是由于扩增或突变所致。 b.检查 Pin1 启动子的转录调控。 (2) 研究Pin1在特定基因转录中的作用 一个。定义 Pin1 磷酸化在与 c-Jun 相互作用中的作用 b.分析 Pin1 如何调节 c-jun 稳定性和功能。 c.建立由 Pin1 特异性激活的基因谱。 (3)研究Pin1在体外和体内癌症发生发展中的作用 一个。分析 Pin1 本身或与 Ras 或 ErbB2 协同的转化活性。 b.在小鼠模型中分析 Pin1 对乳腺癌发生的重要性。 (4)研究抑制Pin1的PPIase活性作为潜在的体外和体内癌症治疗的效果。 该项目旨在培训首席研究员作为独立医师科学家的职业生涯。