Evolution of Melanoma Antigen-A11 (MAGEA11) During Primate Phylogeny

Melanoma antigen-A11 (MAGE-A11) is an X-linked and primate-specific steroid hormone receptor transcriptional coregulator and proto-oncogenic protein whose increased expression promotes the growth of prostate cancer. The MAGEA11 gene is expressed at low levels in normal human testis, ovary, and endometrium, and at highest levels in castration-resistant prostate cancer. Annotated genome predictions throughout the surviving primate lineage show that MAGEA11 acquired three 5' coding exons unique within the MAGEA subfamily during the evolution of New World monkeys (NWM), Old World monkeys (OWM), and apes. MAGE-A11 in all primates has a conserved FXXIF coactivator-binding motif that suggests interaction with p160 coactivators contributed to its early evolution as a transcriptional coregulator. An ancestral form of MAGE-A11 in the more distantly related lemur has significant amino acid sequence identity with human MAGE-A11, but lacks coregulator activity based on the absence of the three 5' coding exons that include a nuclear localization signal (NLS). NWM MAGE-A11 has greater amino acid sequence identity than lemur to human MAGE-A11, but inframe premature stop codons suggest that MAGEA11 is a pseudogene in NWM. MAGE-A11 in OWM and apes has nearly identical 5' coding exon amino acid sequence and conserved interaction sites for p300 acetyltransferase and cyclin A. We conclude that the evolution of MAGEA11 within the lineage leading to OWM and apes resulted in steroid hormone receptor transcriptional coregulator activity through the acquisition of three 5' coding exons that include a NLS sequence and nonsynonymous substitutions required to interact with cell cycle regulatory proteins and transcription factors.