Melanoma Antigen-A11 (MAGE-A11) Enhances Transcriptional Activity by Linking Androgen Receptor Dimers

Abstract

Background: Melanoma antigen-A11 (MAGE-A11) is a primate-specific steroid receptor coregulator. Results: MAGE-A11 mediates the stimulatory effects of cyclic AMP on androgen receptor (AR) transcriptional activity in prostate cancer and can rescue transcriptional activity of complementary inactive AR mutants. Conclusion: MAGE-A11 increases AR transcriptional activity by linking AR dimers. Significance: MAGE-A11 is a new target for prostate cancer treatment.

Proto-oncogene Activity of Melanoma Antigen-A11 (MAGE-A11) Regulates Retinoblastoma-related p107 and E2F1 Proteins

“…These findings suggest that the evolution of MAGE-A11 in primates provides greater regulatory control of steroid receptor transcriptional activity. It was shown recently that MAGE-A11 enhances human AR transcriptional activity by bridging AR dimers in a mechanism that accounts for the dual functions of the AR FXXLF motif in the androgendependent AR NH 2 -and carboxyl-terminal interaction and binding to MAGE-A11 (10).…”

Post-translational Down-regulation of Melanoma Antigen-A11 (MAGE-A11) by Human p14-ARF Tumor Suppressor

“…11) in which MAGE-A11 is central to a protein network involved in human cell growth regulation. We showed previously that MAGE-A11 increases AR transcriptional activity by binding the AR NH 2 -terminal FXXLF motif and recruiting p300 and TIF2 (NCOA2) transcriptional coregulators, which increases androgen-dependent prostate cancer cell growth (1,10,11,38). Here we provide evidence that MAGE-A11 interacts with and is targeted for degradation by the proteasome by the human ARF tumor suppressor.…”

“…The evolution of the MAGE-A11 among primates, its increased expression during androgen deprivation therapy of prostate cancer, its function as an 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). One mechanism for the increase in MAGE-A11 in prostate cancer clinical samples during androgen deprivation therapy and in the CWR22 human xenograft model of prostate cancer that undergoes remission after castration but regrows after castration is progressive hypomethylation of CpG dinucleotides at the transcription start site of the MAGE-A11 gene promoter (2,3).…”

“…5B) relative to control cells and normalized to the ␤-actin protein loading control. Quantitative RT-PCR analysis of MAGE-A11 mRNA extracted from LAPC-4 and HeLa pBabe-control or pBabe-ARF expressing cells using MAGE-A11 and peptidylprolyl isomerase A control specific primers (38) showed no significant change in MAGE-A11 mRNA with the expression of ARF (Fig. 5C).…”

“…LAPC-4 or HeLa cells not treated with retrovirus were killed within 5 days of treatment with 3 g/ml puromycin. Quantitative RT-PCR of RNA extracted using TRIzol from LAPC-4 and HeLa pBabecontrol and pBabe-ARF-expressing cells was performed using sequence specific primers for MAGE-A11 and peptidylprolyl isomerase A control as described (38). Lentivirus shRNA-Endogenous ARF expression was inhibited using a pLK01-modified lentiviral vector that contains an RNA polymerase III-shRNA expression cassette and a puromycin resistance gene under the control of the phosphoglycerate kinase promoter.…”