PIAS PROTEINS IN ANDROGEN SIGNALING AND PROSTATE CANCER

University Of California Los Angeles, Los Angeles CA

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Abstract

DESCRIPTION (provided by applicant): Prostate cancer is the most frequently diagnosed cancer in American men. Androgen plays an important role in the development and growth of prostate carcinomas. Today, the most effective treatment for advanced prostate cancer is androgen ablation. However, after a period of remission, a relapse occurs because of acquisition of androgenindependent tumor growth. Cofactors of androgen receptor (AR) can influence AR-mediated gene activation by interaction with general transcription factors or remodeling chromatin. My laboratory has identified a family of proteins named PIAS (protein inhibitor of activated STAT) which can modulate the activity of STAT (signal transducer and activator of transcription) transcription factors upon cytokine stimulation. Recently, we and others have shown that PIAS proteins can regulate AR both positively and negatively. The overall goal of this proposal is to study the role of PIAS proteins in androgen signaling and prostate tumor progression. First, we will investigate the molecular mechanism of PIAS-mediated effects on androgen signaling. Specifically, we will test our hypothesis that PIAS may act as coactivator/corepressor of AR. Mutational analysis will be performed to identify PIAS-AR interaction domains as well as the activation/repression domains of PIAS. The possible interactions of PIAS with other coregulator complexes will be studied by analyzing PIAS-interacting proteins. In addition, we will examine if PIAS proteins can affect the DNA binding activity of AR. The molecular basis of the specific efects of PIAS1 and PIASy on ARmediated gene transcription will be studied by domain swapping analysis. Second, we will test our hypothesis that PIAS proteins may be abnormally regulated in prostate cancer. The expression of PIAS mRNAs and proteins in malignant human prostate tissues and prostate tumor xenografts will be analyzed. Third, prostate cancer cell lines with increased or decreased PIAS expression will be established and used to examine the effects of PIAS on androgen response. STAT signaling and its possible effect on AR response will also be examined. Finally, prostate cell lines expressing various wild type and mutant PIAS proteins will be injected into immune deficient SCID mice. The effects of PIAS proteins on prostate tumor progression will be examined. Studies on the role of PIAS proteins in androgen signaling and prostate cancer may enhance the development of effective therapies for patients with hormonerefractory disease.