MAGE-A cancer/testis antigens inhibit MDM2 ubiquitylation function and promote increased levels of MDM4

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

Social networks and mental health among a farming population

Aims: The study investigated the associations between mental health and measures of community support, social support networks, sense of place, adversity, and perceived problems in a rural Australian population. There was a specific focus on farming communities due to previous qualitative research by the authors indicating distress by farmers in response to drought (Sartore et al. Aust Fam Phys 36(12), 990–993, 2007). Method: A survey was mailed to adults randomly selected from the Australian Electoral Roll and residing within four local government areas (LGAs) of varying remoteness in rural New South Wales (NSW). Survey measures included: support networks and community attachment; recent stressors (including drought-related stress); and measures of health and related functioning. The Kessler-10 provided an index of current psychological distress. Results: The sample (n = 449; response rate 24%) was predominantly female (58.4%) and 18.9% were farmers or farm workers. Moderate to very high psychological distress was reported for 20.7% of the sample. Half (56.1%) of all respondents, and specifically 71.8% of farmers or farm workers, reported high levels of perceived stress due to drought. Psychological distress was associated with recent adverse life events, increased alcohol use and functional impairment. Hierarchical regression analysis demonstrated an independent effect of the number of stressful life events including drought related stress, perceived social support (community and individual), alcohol use and physical functioning ability on levels of psychological distress. This model accounted for 43% of the variance in current levels of distress. Lower community support had a more marked impact on distress levels for non-farming than farming participants. Conclusions: This study has highlighted the association between unique rural community characteristics and rural stressors (such as drought) and measures of mental health, suggesting the important mediating role of social factors and community characteristics. The results illustrate the importance of addressing subgroup differences in the role of social capital in mental health