Role of the Prolylisomerase Pin1 in Oncogenesis

描述（由申请人提供）：Pin 1可能通过结合和异构化磷酸化S/T-P基序来调节磷蛋白亚类的功能（11-20）。 Pin 1的抑制导致肿瘤细胞的生长停滞，并导致阿尔茨海默病中的神经元死亡（11）。 我发现Pin 1在75%的乳腺癌标本中过表达，并且它与Ras信号传导合作增加c-Jun对细胞周期蛋白D1的转录活性（12）。 Pin 1还通过调节β-连环蛋白的周转和亚细胞定位引起细胞周期蛋白D1的积累（81）。 基因敲除小鼠Pin 1功能的丧失模拟细胞周期蛋白D1缺失表型，导致乳腺发育严重缺陷（84）。 鉴于Ras信号和细胞周期蛋白D1在肿瘤发生中的重要作用，我们的研究结果表明，Pin 1的过度表达可能会促进乳腺癌的生长。 本提案旨在检验这一假设，具体目标如下： (1)研究Pin 1在乳腺癌中的过表达机制 a.检查Pin 1的过表达是否是由于扩增或突变。 B.检测Pin 1启动子的转录调控。 (2)研究Pin 1在特定基因转录中的作用 a.确定Pin 1磷酸化在其与c-Jun相互作用中的作用 B.分析Pin 1如何调节c-jun的稳定性和功能。 C.建立Pin 1特异性激活的基因谱。 (3)研究Pin 1在体外和体内肿瘤发生中的作用 a.分析Pin 1本身或与Ras或ErbB 2协同作用的转化活性。 B.在小鼠模型中分析Pin 1对乳腺癌发展的意义。 (4)研究抑制Pin 1的PPIase活性作为潜在癌症治疗的体外和体内效果。 该项目旨在培养主要研究者作为独立的医生科学家的职业生涯。

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.