Emerging roles of the MAGE protein family in stress response pathways

The melanoma antigen (MAGE) proteins all contain a MAGE homology domain (MHD). MAGE genes are conserved in all eukaryotes and have expanded from a single gene in lower eukaryotes to approximately 40 genes in humans and mice. While some MAGEs are ubiquitously expressed in tissues, others are expressed in only germ cells with aberrant re-activation in multiple cancers. Much of the initial research on MAGEs focused on exploiting their antigenicity and restricted expression pattern to target them with cancer immunotherapy. Beyond their potential clinical application and role in tumorigenesis, recent studies have shown that MAGE proteins regulate diverse cellular and developmental pathways, implicating them in many diseases besides cancer, including lung, renal, and neurodevelopmental disorders. At the molecular level, many MAGEs bind to E3 RING ubiquitin ligases and, thus, regulate their substrate specificity, ligase activity, and subcellular localization. On a broader scale, the MAGE genes likely expanded in eutherian mammals to protect the germline from environmental stress and aid in stress adaptation, and this stress tolerance may explain why many cancers aberrantly express MAGEs. Here, we present an updated, comprehensive review on the MAGE family that highlights general characteristics, emphasizes recent comparative studies in mice, and describes the diverse functions exerted by individual MAGEs.