The androgen receptor (AR), a member of a superfamily of ligand-activated nuclear transcription factors, mediates the biological functions of androgens in prostate development, growth, function, tumorigenesis, and cancer progression. Androgen ablation therapy, while effective at early androgen-dependent stages, fails at the androgen-independent stages of advanced prostate cancer. Although these tumors are clinically androgen-independent, they appear to remain androgen receptor-dependent through mechanisms that are not effectively blocked by androgen deprivation therapy. Androgen-independent progression has been associated with mutations and amplification of the androgen receptor gene and with activation of intracellular signaling pathways that stimulate androgen receptor function. A detailed understanding of the molecular mechanisms by which androgen receptor activates/represses key target genes would provide insights into the role of androgens in growth and development of the prostate and in development and progression of prostate cancer. Androgen receptor direct target genes that play key regulatory roles in prostate development, maintenance, and tumorigenesis are poorly defined. The general objective of this proposal is to identify AR direct target genes as a basis for understanding AR functions in survival, differentiation, and proliferation of cells of the prostate, as well as early events leading to prostate cancer, and to investigate the mechanism of action of AR and various identified AR cofactors on these genes. Toward this objective we will (i) identify genes that are targeted directly by AR; (ii) determine the gene specificity of various identified AR cofactors; (iii) investigate AR and cognate cofactor functions in cell-free transcription systems reconstituted with general initiation factors. This approach may provide insights into development of new drugs that target the androgen receptor pathway downstream of the point of ligand-receptor interaction.
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