Interplay Between TGFβ1 Signaling and Cancer-Testis Antigen MAGEB2: A New Thorn in Cancer's Side?

The Melanoma Antigen Gene (MAGE) family of proteins is the largest family of cancer-testis antigens (CTAs) and shares a MAGE homology domain (MHD). MAGE proteins are divided into Type I and Type II MAGEs depending on their chromosomal location and expression patterns. Type I MAGEs are true CTAs. MAGEB2 is a Type I MAGE, belonging to the MAGEB subfamily, and unlike some MAGE proteins, has not been found to bind to and enhance E3 ligase activity. MAGEB2 has been discovered to be an RNA-binding protein that serves to protect spermatogonial cells in the testis from extraneous stressors. We have discovered that MAGEB2 is necessary and sufficient for the proliferation of cells and is expressed by the differential DNA methylation of its gene promoter. Furthermore, we identified JunD as the transcription factor that regulates MAGEB2 expression. When expressed, MAGEB2 suppresses transforming grown factor-β1 (TGFβ1) signaling by decreasing mRNA levels of Thrombospondin-1 (TSP-1). TSP-1 is an anti-angiogenic protein that activates TGFβ1. Restoring levels of TSP-1 or TGFβ1 results in the inability of MAGEB2 to drive proliferation, suggesting that MAGEB2-expressing tumors might be more susceptible to therapies that induce or activate TSP-1 or TGFβ1 signaling.