Abstract
Melanoma antigen A (MAGE-A) proteins comprise a structurally and biochemically similar sub-family of Cancer/Testis antigens that are expressed in many cancer types and are thought to contribute actively to malignancy. MAGE-A proteins are established regulators of certain cancer-associated transcription factors, including p53, and are activators of several RING finger-dependent ubiquitin E3 ligases. Here, we show that MAGE-A2 associates with MDM2, a ubiquitin E3 ligase that mediates ubiquitylation of more than 20 substrates including mainly p53, MDM2 itself, and MDM4, a potent p53 inhibitor and MDM2 partner that is structurally related to MDM2. We find that MAGE-A2 interacts with MDM2 via the N-terminal p53-binding pocket and the RING finger domain of MDM2 that is required for homo/hetero-dimerization and for E2 ligase interaction. Consistent with these data, we show that MAGE-A2 is a potent inhibitor of the E3 ubiquitin ligase activity of MDM2, yet it does not have any significant effect on p53 turnover mediated by MDM2. Strikingly, however, increased MAGE-A2 expression leads to reduced ubiquitylation and increased levels of MDM4. Similarly, silencing of endogenous MAGE-A expression diminishes MDM4 levels in a manner that can be rescued by the proteasomal inhibitor, bortezomid, and permits increased MDM2/MDM4 association. These data suggest that MAGE-A proteins can: (i) uncouple the ubiquitin ligase and degradation functions of MDM2; (ii) act as potent inhibitors of E3 ligase function; and (iii) regulate the turnover of MDM4. We also find an association between the presence of MAGE-A and increased MDM4 levels in primary breast cancer, suggesting that MAGE-A-dependent control of MDM4 levels has relevance to cancer clinically.
Highlights
Melanoma-associated antigens (MAGE) were initially discovered as cancer-associated antigens in melanoma patients [1] and are known to comprise a super-family of more than 60 genes in humans [2,3]
We find that MAGE-A2 interacts with MDM2 via the N-terminal p53-binding pocket and the RING finger domain of MDM2 that is required for homo/heterodimerization and for E2 ligase interaction
Melanoma antigen A (MAGE-A) comprises an 11-member sub-family of the broader family of MAGE proteins which are characterised by the presence of a MAGE-homology domain [3]
Summary
Melanoma-associated antigens (MAGE) were initially discovered as cancer-associated antigens in melanoma patients [1] and are known to comprise a super-family (encompassing several sub-families) of more than 60 genes in humans [2,3]. Consistent with a cancer-promoting role, MAGE-A expression stimulates cell cycle progression, migration rate and invasiveness of cultured cells in vitro and can promote increases in tumor size and in the number and size of metastatic foci in animal models [7,8]. These data support the idea that MAGE-A expression may contribute towards malignancy
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