The focus of this proposal is on Androgen Receptor Trapped clone-27 (ART-27) and Unconventional prefoldin RBP5 Interactor (URI), two proteins that interact with one another and have a major impact on transcriptional regulation through the Androgen Receptor (AR). During prostate development in humans, ART-27 is expressed in differentiated luminal epithelial cells but is not detected in undifferentiated epithelial cell precursors, suggesting a role for ART-27 in AR-mediated growth suppression and differentiation. Consistent with a growth suppressive function, ART-27 expression levels are decreased in human prostate cancer and regulated expression of ART-27 in the androgen sensitive LNCaP prostate cancer cell line inhibits androgen- mediated cellular proliferation. Moreover, a somatic alteration in AR (AR P340L) derived from a prostate cancer shows diminished capacity to enhance ART-27 mediated AR-transcriptional activation. Further, a recent report and our two-hybrid results indicate that ART-27 associates with Unconventional prefoldin RBP5 Interactor (URI) forming complexes with RPB5, a subunit of RNA polymerase, to control transcription programs. URI is implicated in maintenance of genomic integrity and a recent profiling of staged cancer samples indicates that URI is one a group of genes up-regulated in Prostatic Intraepithelial Neoplasia (PIN), a proliferative lesion thought to be a precursor to prostate cancer. Based on these findings, we hypothesize that ART-27 is a cell type specific and developmentally regulated protein that links AR to the URI transcriptional regulatory complex and affects AR target genes important in prostate growth regulation. To test this hypothesis we propose to: 1) Identify ART-27-dependent AR- target genes and the impact of ART-27 and URI on cell cycle progression 2) Determine if ART-27 and URI function independently to direct AR-mediated gene transcription and 3) Elucidate the role of ART-27 in prostate epithelial cell growth and differentiation in vivo. The over-riding hypothesis of this proposal is that AR cofactors modulate specific programs of gene transcription that aid and abet tumor progression. ART-27 and URI are novel members of a transcription complex that clearly play an important role in AR signaling, yet very little is known about the function of these proteins in the prostate. The long-term goal is to understand how AR directs cell metabolism and differentiation in some cellular contexts and proliferation in others.
While prostate cancers are initially treatable by anti-hormone therapy, they inevitably become resistant to therapy resulting in few treatment options. The focus of this grant is to understand the biology leading to anti- hormone resistant prostate cancer.
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|Mita, Paolo; Savas, Jeffrey N; Briggs, Erica M et al. (2016) URI Regulates KAP1 Phosphorylation and Transcriptional Repression via PP2A Phosphatase in Prostate Cancer Cells. J Biol Chem 291:25516-25528|
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|Ha, S; Iqbal, N J; Mita, P et al. (2013) Phosphorylation of the androgen receptor by PIM1 in hormone refractory prostate cancer. Oncogene 32:3992-4000|
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