Title |
Post-translational Down-regulation of Melanoma Antigen-A11 (MAGE-A11) by Human p14-ARF Tumor Suppressor*
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Published in |
Journal of Biological Chemistry, September 2015
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DOI | 10.1074/jbc.m115.663641 |
Pubmed ID | |
Authors |
John T Minges, Gail Grossman, Ping Zhang, Tal Kafri, Elizabeth M Wilson |
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 increases AR and E2F1 transcriptional activity and promotes the development of castration-resistant prostate cancer. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 25 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Ph. D. Student | 7 | 28% |
Student > Bachelor | 3 | 12% |
Professor | 2 | 8% |
Researcher | 2 | 8% |
Student > Master | 2 | 8% |
Other | 5 | 20% |
Unknown | 4 | 16% |
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Psychology | 2 | 8% |
Chemistry | 1 | 4% |
Other | 0 | 0% |
Unknown | 7 | 28% |