Role of PIASy in Androgen Signaling and Prostate Cancer

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DESCRIPTION (provided by applicant): Aberrant activation of the androgen-signaling pathway plays a central role in prostate cancer development and progression. The molecular details controlling androgen-dependent gene activation in prostate cancer, in general, and the role of androgen receptor repressors, in particular, remain largely unexplored. Our laboratory has identified a family of proteins as inhibitors of STAT (signal transducer and activator of transcription) signaling named PIAS (protein inhibitor of activated STAT). Our preliminary results show that one member of the PIAS family, PIASy, is a potent repressor of androgen signaling. PIASy binds to the DNA binding domain of androgen receptor (AR), but does not affect the ability of AR to bind to DNA. We also show that PIASy is expressed in human prostate cancer and that the level of PIASy is decreased along with progression to androgen-independence in some prostate cancer xenografts. The overall goals of this proposal are to study the molecular basis of the PIASy inhibitory effect on androgen signaling and explore the hypothesis that down regulation of PIASy, as an AR repressor, is involved in the progression to androgen-independent prostate cancer growth. The proposed research will be performed at the laboratory of Dr. Ke Shuai under the additional guidance of Dr. Charles Sawyers both at the University of California at Los Angeles. The experiments outlined will enable the candidate to obtain rigorous training in molecular biology techniques and apply this knowledge towards understanding prostate cancer. The candidate is also enrolled in the Molecular Biology Interdepartmental doctoral program at UCLA and is expected to complete the requirements for a doctorate in molecular biology during the first year of this proposal. As a medical oncologist, the candidate?s career goal is to combine research in the fields of signal transduction and tumor biology to understand and treat prostate cancer.