The androgen receptor (AR) is an essential transcription factor in prostate cancer development and progression that mediates its effects through interactions with coregulatory proteins. Melanoma antigen gene protein-11 (IVlAGE-11) Is an AR coregulator and IVIAGE gene member family of cancer-testis antigens expressed in androgen-dependent prostate cancer and overexpressed in castration-recurrent prostate cancer. MAGE-11 interacts with the AR Nl-l2-terminal FXXLF motif to increase AR transcriptional activity. Described in this proposal are studies to identify the mechanisms whereby MAGE-11 contributes to AR reactivation and promotion of recurrent prostate cancer growth. The studies test the hypothesis that MAGE-11 is a product of a proto-oncogene that increases AR transcriptional activity through interactions with the retinoblastoma pocket proteins, Rb and/or p107 (Rb/p107).
Aim 1 in collaboration with Project 1 will establish the requirement for MAGE-11 in AR mediated prostate cancer cell growth using lentiviral vectors to silence and recover MAGE-11 expression. The cell cycle regulation of MAGE-11 and effects of MAGE-11 knockdown on the cell cycle, cell senescence and/or apoptosis will be determined. Lentiviral overexpression of MAGE-11 will be performed to simulate the cellular milieu of recurrent prostate cancer.
Aim 2 pursues preliminary evidence that MAGE-11 sequesters the hypophosphorylated form of Rb/p107 to promote cell cycle progression. The ability of MAGE-11 to interact with Rb/p107 will be assessed with respect to the phosphorylation of MAGE-11 and Rb/p107 and the coregulatory effects of MAGE-11 and Rb/p107 on AR transcriptional activity.
Aim 3 investigates functional effects of AR and MAGE-11 interactions with Skp2 (S phase kinase-associated protein 2) to modulate Skp2 activity and degradation, Rb/p107 effects on the Skp2-p27-Kip1 pathway and the E2F transcription factor-regulated gene network required for the G1/S transition. The studies are based on preliminary evidence that AR and MAGE-11 stabilize Skp2. The overall goal of the proposed experimental plan is to establish the mechanisms by which MAGE-11 contributes to the reactivation of AR to promote the growth and progression of prostate cancer.
Prostate cancer is a multifactorial disease in which the androgen receptor (AR) and its coregulators have a central role. Recent studies identified MAGE-11 as a regulatory protein that links AR to cell cycle progression and prostate cancer cell proliferation. The proposed mechanistic studies may provide a basis for the development of new treatment strategies to arrest castration-recurrent growth of prostate cancer.
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