MAGE genes were first described as cancer-testis antigens, which are silenced in normal adult tissues but aberrantly expressed in tumor cells. The short peptides, derived from the degradation of MAGE transcripts, are the source of antigens that cause tumor rejection reactions when presented in the context of major histocompatibility complex. The recent discovery of a subset of genes that contain the structurally conserved MAGE homology domain (MHD) has accelerated the investigation into the normal function of MAGE genes. This new type of MAGE gene is normally expressed in embryonal and adult tissue, especially the brain. MAGE-D1, also known as NRAGE or Dlxin-1, functions as an adaptor protein that mediates multiple signaling pathways, including NGFR (p75NTR) and UNC5H1-induced apoptosis and Dlx/Msx-mediated transcription. Loss of a different MAGE family member, Necdin, which works as a cell cycle regulator, may play a role in the pathogenesis of Prader-Willi syndrome, a neurobehavioral disorder. In this article, the authors discuss recent findings concerning the structure and function of new MAGE genes, primarily focusing on MAGE-D1. Because some MAGE-D subfamily proteins share significant homology within the MHD, these recent discoveries on MAGE-D1 may give insight into the function of other MAGE-D proteins.
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