Role of the Prolylisomerase Pin1 in Oncogenesis

描述（由申请人提供）：Pin1调节一组磷酸化蛋白的功能，可能是通过结合和异构化磷酸化的S/T-P基序（11-20）。抑制Pin1导致肿瘤细胞生长停滞，并导致阿尔茨海默病的神经元死亡（11）。我发现Pin1在75%的乳腺癌标本中过表达，并且它与Ras信号一起增加c-Jun对cyclin D1的转录活性（12）。Pin1也通过调节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）。敲除小鼠Pin1功能的丧失模仿了cyclin D1无表型，并导致乳腺发育的严重缺陷（84）。考虑到Ras信号和cyclin D1在肿瘤发生中的重要作用，我们的研究结果表明Pin1的过表达可能促进乳腺癌的生长。

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.