title: Gain in transcriptional activity by primate-specific coevolution of melanoma antigen-A11 and its interaction site in androgen receptor.
abstract: Male sex development and growth occur in response to high affinity androgen binding to the androgen receptor (AR). In contrast to complete amino acid sequence conservation in the AR DNA and ligand binding domains among mammals, a primate-specific difference in the AR NH(2)-terminal region that regulates the NH(2)- and carboxyl-terminal (N/C) interaction enables direct binding to melanoma antigen-A11 (MAGE-11), an AR coregulator that is also primate-specific. Human, mouse, and rat AR share the same NH(2)-terminal (23)FQNLF(27) sequence that mediates the androgen-dependent N/C interaction. However, the mouse and rat AR FXXLF motif is flanked by Ala(33) that evolved to Val(33) in primates. Human AR Val(33) was required to interact directly with MAGE-11 and for the inhibitory effect of the AR N/C interaction on activation function 2 that was relieved by MAGE-11. The functional importance of MAGE-11 was indicated by decreased human AR regulation of an androgen-dependent endogenous gene using lentivirus short hairpin RNAs and by the greater transcriptional strength of human compared with mouse AR. MAGE-11 increased progesterone and glucocorticoid receptor activity independently of binding an FXXLF motif by interacting with p300 and p160 coactivators. We conclude that the coevolution of the AR NH(2)-terminal sequence and MAGE-11 expression among primates provides increased regulatory control over activation domain dominance. Primate-specific expression of MAGE-11 results in greater steroid receptor transcriptional activity through direct interactions with the human AR FXXLF motif region and indirectly through steroid receptor-associated p300 and p160 coactivators.
authors: Laboratories for Reproductive Biology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7500, USA.
authors: Qiang
authors: Q
authors: Liu
authors: Shifeng
authors: S
authors: Su
authors: Amanda J
authors: AJ
authors: Blackwelder
authors: John T
authors: JT
authors: Minges
authors: Elizabeth M
authors: EM
authors: Wilson
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D002522:Chlorocebus aethiops; D019143:Evolution, Molecular; D005786:Gene Expression Regulation / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051381:Rats; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D014158:Transcription, Genetic / Q000502:physiology*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000951:Antigens, Neoplasm; C110882:MAGEA11 protein, human; D009363:Neoplasm Proteins; D011944:Receptors, Androgen; D050880:p300-CBP Transcription Factors