Role of the Prolylisomerase Pin1 in Oncogenesis

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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.