Role of the Prolylisomerase Pin1 in Oncogenesis

描述(申请人提供)：PIN1可能通过结合和异构化其磷酸化的S/T-P基序(11-20)来调节一亚组磷蛋白的功能。抑制Pin1导致肿瘤细胞生长停滞，并导致阿尔茨海默病神经元死亡(11)。我发现Pin1在75%的乳腺癌标本中过表达，并且它与RAS信号在增加c-jun对细胞周期蛋白D1(12)的转录活性方面具有协同作用。Pin1还通过调节β-连环蛋白(81)的周转和亚细胞定位而导致细胞周期蛋白D1的积聚。基因敲除小鼠中Pin1功能的丧失模仿细胞周期蛋白D1缺失的表型，并导致乳腺发育的严重缺陷(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，我们的结果提示Pin1的过表达可能促进乳腺癌的生长。 这项提议旨在通过以下具体目标来检验这一假设： (1)探讨Pin1在乳腺癌中过表达的机制 A.检查Pin1的过度表达是由于扩增还是突变。 B.检测Pin1启动子的转录调控。 (2)研究Pin1在特定基因转录中的作用 A.确定Pin1磷酸化在其与c-jun相互作用中的作用 B.分析Pin1是如何调节c-jun的稳定性和功能的。 C.建立由Pin1特异激活的基因图谱。 (3)研究Pin1在体内外肿瘤发生发展中的作用。 A.分析Pin1自身或与RAS或ErbB2协同转化的活性。 B.在小鼠模型中分析Pin1在乳腺癌发生中的意义。 (4)研究抑制PIN1‘S PPIase活性作为潜在的肿瘤治疗方法的体内外效应。 该项目旨在培训首席研究员，使其成为一名独立的内科科学家。

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.