Regulation of gene expression by the androgen receptor (AR) involves the association and action of transcriptional coregulatory proteins. Although a plethora of AR-interacting proteins have been identified, the physiological and pathological roles fulfilled by these factors in AR-mediated signaling pathways remain poorly understood. The goal of this application is to investigate and characterize the involvement of specific AR-coregulatory factors during normal prostate growth and the progression of prostate tumorigenesis. Given that prostate cancer cells are initially androgen-dependent and eventually progress into androgen-independent cells, we hypothesize that neoplastic changes in AR signaling pathways and/or the AR protein itself can abnormally affect the specific types of coregulatory protein complexes that bind to the receptor. To address these issues, we will generate stable FLAG epitope-tagged AR (f:AR) expressing cell lines from immortalized primary prostate cells (normal and malignant) and from metastatic prostate tumor cells. The lines will serve as biological tools with which we will immunoaffinity purify f:AR from hormone treated (and untreated) cells and subsequently examine and characterize the AR-associated proteins using a number of biochemical techniques. Our specific goals are to: (1) Determine whether distinct types of transcriptional coregulatory proteins are differentially associated with f:AR in normal versus malignant prostate cells. Stable f:AR-expressing prostate lines will be cultured in the presence (or absence) of distinct androgens and anti-androgens; f:AR-cofactor complexes will be purified and characterized by silver stain, Western blotting and mass spectrometry. (2) Determine whether androgen-independent signaling pathways induce f:AR-cofactor complex assembly in normal and malignant prostate cells. These studies will examine whether activation of specific receptor tyrosine kinases (previously implicated in prostate cancer and androgen-independent growth) can trigger specific f: AR-cofactor complex formation in the absence of AR ligands. (3) Determine whether pathologically associated mutations/polymorphisms in the AR gene affect f:AR-cofactor assembly. The f:AR cDNA will be subjected to site-directed mutagenesis and subsequently stably introduced into prostate cells. The mutated f:AR will be purified from ligand-treated cells and the associated cofactors identified and characterized. In summary, the studies outlined here should increase our fundamental understanding of the role of coregulatory factors in AR-mediated signaling pathways and potentially identify and define new targets for therapeutic agents in the treatment of prostate cancer.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZDK1-GRB-7 (O1))
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Margolis, Ronald N
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University of Medicine & Dentistry of NJ
Schools of Medicine
United States
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Wang, Qianben; Udayakumar, T S; Vasaitis, Tadas S et al. (2004) Mechanistic relationship between androgen receptor polyglutamine tract truncation and androgen-dependent transcriptional hyperactivity in prostate cancer cells. J Biol Chem 279:17319-28
Wang, Qianben; Sharma, Dipali; Ren, Yunsheng et al. (2002) A coregulatory role for the TRAP-mediator complex in androgen receptor-mediated gene expression. J Biol Chem 277:42852-8