Abstract
X-linked primate-specific melanoma antigen-A11 (MAGE-A11) is a human androgen receptor (AR) coactivator and proto-oncogene expressed at low levels in normal human reproductive tract tissues and at higher levels in castration-resistant prostate cancer where it is required for androgen-dependent cell growth. In this report, we show that MAGE-A11 is targeted for degradation by human p14-ARF, a tumor suppressor expressed from an alternative reading frame of the p16 cyclin-dependent kinase inhibitor INK4a/ARF gene. MAGE-A11 degradation by the proteasome was mediated by an interaction with p14-ARF and was independent of lysine ubiquitination. A dose-dependent inverse relationship between MAGE-A11 and p14-ARF correlated with p14-ARF inhibition of the MAGE-A11-induced increase in androgen-dependent AR transcriptional activity and constitutive activity of a splice variant-like AR. Reciprocal stabilization between MAGE-A11 and AR did not protect against degradation promoted by p14-ARF. p14-ARF prevented MAGE-A11 interaction with the E2F1 oncoprotein and inhibited the MAGE-A11-induced increase in E2F1 transcriptional activity. Post-translational down-regulation of MAGE-A11 promoted by p14-ARF was independent of HDM2, the human homologue of mouse double minute 2, an E3 ubiquitin ligase inhibited by p14-ARF. However, MAGE-A11 had a stabilizing effect on HDM2 in the absence or presence of p14-ARF and cooperated with HDM2 to increase E2F1 transcriptional activity in the absence of p14-ARF. We conclude that degradation of MAGE-A11 promoted by the human p14-ARF tumor suppressor contributes to low levels of MAGE-A11 in nontransformed cells and that higher levels of MAGE-A11 associated with low p14-ARF increase AR and E2F1 transcriptional activity and promote the development of castration-resistant prostate cancer.
Highlights
Melanoma antigen-A11 (MAGE-A11) is a primate-specific steroid receptor coregulator and proto-oncogene expressed at increased levels in castration-resistant prostate cancer
Based on the ability of MAGE-A11 to stabilize and increase E2F1 transcriptional activity, and the ARF tumor suppressor to promote E2F1 degradation and inhibit E2F1 transcriptional activity [41, 42], we investigated whether MAGE-A11 is a direct target of human ARF or proteins regulated by ARF
The evolution of the MAGE-A11 among primates, its increased expression during androgen deprivation therapy of prostate cancer, its function as an androgen receptor (AR) coregulator, and the requirement for MAGE-A11 in prostate cancer cell growth support the concept that MAGE-A11 is a proto-oncogene that hyperactivates human AR and promotes the development of castration-resistant prostate cancer [38]
Summary
Melanoma antigen-A11 (MAGE-A11) is a primate-specific steroid receptor coregulator and proto-oncogene expressed at increased levels in castration-resistant prostate cancer. X-linked primate-specific melanoma antigen-A11 (MAGEA11) is a human androgen receptor (AR) coactivator and protooncogene expressed at low levels in normal human reproductive tract tissues and at higher levels in castration-resistant prostate cancer where it is required for androgen-dependent cell growth. We conclude that degradation of MAGE-A11 promoted by the human p14-ARF tumor suppressor contributes to low levels of MAGE-A11 in nontransformed cells and that higher levels of MAGE-A11 associated with low p14-ARF increase AR and E2F1 transcriptional activity and promote the development of castration-resistant prostate cancer. Neither mouse nor rat AR Ala or human AR Val is required for the FXXLF motif-mediated androgen-dependent AR NH2- and COOH-terminal interaction These findings suggest that the increase in human AR transcriptional activity resulting from the coactivator activity of MAGE-A11 evolved more recently among primates than evolution of the androgendependent AR NH2- and COOH-terminal interaction. The findings suggest that ARF maintains normal low levels of MAGE-A11 to limit cell proliferation and preserve the nontransformed phenotype, whereas low levels of ARF in prostate cancer cells contribute to higher levels of MAGE-A11 that promote the development of castration-resistant prostate cancer
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