title: Melanoma antigen-A11 (MAGE-A11) enhances transcriptional activity by linking androgen receptor dimers.
abstract: Prostate cancer growth and progression depend on androgen receptor (AR) signaling through transcriptional mechanisms that require interactions with coregulatory proteins, one of which is the primate-specific steroid receptor coregulator melanoma antigen-A11 (MAGE-A11). In this report, we provide evidence how increased expression of MAGE-A11 during prostate cancer progression enhances AR signaling and prostate cancer growth. MAGE-A11 protein levels were highest in castration-recurrent prostate cancer. The cyclic AMP-induced increase in androgen-dependent and androgen-independent AR transcriptional activity correlated with an increase in MAGE-A11 and was inhibited by silencing MAGE-A11 expression. MAGE-A11 mediated synergistic AR transcriptional activity in LAPC-4 prostate cancer cells. The ability of MAGE-A11 to rescue transcriptional activity of complementary inactive AR mutants and promote coimmunoprecipitation between unlike forms of AR suggests that MAGE-A11 links transcriptionally active AR dimers. A model for the AR·MAGE-A11 multidimeric complex is proposed in which one AR FXXLF motif of the AR dimer engages in the androgen-dependent AR NH(2)- and carboxyl-terminal interaction, whereas the second FXXLF motif region of the AR dimer interacts with dimeric MAGE-A11. The AR·MAGE-A11 multidimeric complex accounts for the dual functions of the AR FXXLF motif in the androgen-dependent AR NH(2)- and carboxyl-terminal interaction and binding MAGE-A11 and for synergy between reported AR splice variants and full-length AR. We conclude that the increased expression of MAGE-A11 in castration-recurrent prostate cancer, which is enhanced by cyclic AMP signaling, increases AR-dependent growth of prostate cancer by MAGE-A11 forming a molecular bridge between transcriptionally active AR dimers.
authors.affiliation: Laboratories for Reproductive Biology, Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27599-7500, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Minges
authors.forename: Shifeng
authors.initials: S
authors.lastname: Su
authors.forename: Gail
authors.initials: G
authors.lastname: Grossman
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Blackwelder
authors.forename: Elena A
authors.initials: EA
authors.lastname: Pop
authors.forename: James L
authors.initials: JL
authors.lastname: Mohler
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Wilson
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D055503:Protein Multimerization; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: C410798:AR protein, human; D000951:Antigens, Neoplasm; C110882:MAGEA11 protein, human; D009363:Neoplasm Proteins; D011944:Receptors, Androgen; D000242:Cyclic AMP