Fig. 2

MAGEs function as transcription regulators. (1). MAGEs regulate KAP1 activity as transcription activator. a KAP1 functions as a molecular scaffold for gene-specific silencing by targeting of specific promoters through the KRAB protein zinc finger motifs, promotion of histone deacetylation via the NuRD/histone deacetylase complex, histone H3-K9 methylation via SETDB1 and recruitment of HP1 protein. b MAGE-C2 binds KAP1 and increases ATM-induced phosphorylation of KAP1-Serine 824 (Ser824), thus enhancing DNA damage repair and tumor activation. (2). a MAGEs binding to KAP1 induces p53 degradation and repression of p53 targeted genes. b MAGE-A proteins can directly interact with p53 leading to obstruction of p53 binding to p53-responsive promoters. c MAGE-A proteins also inhibit p53 transcription functions by recruiting HDAC3 to the binding sites of p53 promoter. (3). MAGEs promote prostate cancer progression via increasing AR activity. MAGE-A11 binds NH2-terminal FXXLF motif of AR and increases AR transcriptional activity by modulating AR interdomain interaction. EGFs stabilize AR-MAGE-A11 complex through the site-specific phosphorylation of Thr-360 and subsequent ubiquitinylation of Lys-240, Lys-245 within MAGE homology domain.