Role of the Prolylisomerase Pin1 in Oncogenesis

Prolylisomerase Pin1 在肿瘤发生中的作用

• 批准号: 6838810
• 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/6838810
• 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调节磷蛋白子集的功能，大概是通过结合和异构化磷酸化的S/T-P基序（11-20）。 PIN1的抑制会导致肿瘤细胞的生长停滞，并导致阿尔茨海默氏病的神经元死亡（11）。 我发现PIN1在75％的乳腺癌标本中过表达，并且它与RAS信号合作，以增加C-Jun对Cyclin d1的转录活性（12）。 PIN1还通过调节β-catenin的周转和亚细胞定位来引起细胞周期蛋白D1的积累（81）。 敲除小鼠中PIN1功能的丧失模仿细胞周期蛋白D1 NULL表型，并在乳腺发育中导致严重缺陷（84）。 鉴于RAS信号传导和Cyclin D1在肿瘤发生中的关键作用，我们的结果表明PIN1的过表达可能促进乳腺癌的生长。 该建议是通过以下特定目的检验该假设： （1）检查乳腺癌中PIN1过表达的机制 一个。检查PIN1的过表达是由于扩增还是突变引起的。 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。建立特异性通过PIN1激活的基因的轮廓。 （3）研究PIN1在体外和体内癌症发展中的作用 一个。分析PIN1本身或与RAS或ERBB2合作的转化活性。 b。分析PIN1对小鼠模型中乳腺癌发育的重要性。 （4）研究抑制PIN1的PPIASE活性作为体外和体内潜在癌症治疗的影响。 该项目旨在培训主要研究人员的职业生涯，担任独立医师科学家。