Melanoma antigen-A11 (MAGE-A11) enhances transcriptional activity by linking androgen receptor dimers

J Biol Chem. 2013 Jan 18;288(3):1939-52. doi: 10.1074/jbc.M112.428409. Epub 2012 Nov 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Antigens, Neoplasm / genetics*
  • Antigens, Neoplasm / metabolism
  • Binding Sites
  • COS Cells
  • Chlorocebus aethiops
  • Cyclic AMP / metabolism
  • Humans
  • Male
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Melanoma / pathology
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Plasmids
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Protein Binding
  • Protein Multimerization
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism
  • Transcription, Genetic
  • Transcriptional Activation*
  • Transfection
  • Tumor Cells, Cultured

Substances

  • AR protein, human
  • Antigens, Neoplasm
  • MAGEA11 protein, human
  • Neoplasm Proteins
  • Receptors, Androgen
  • Cyclic AMP