Abstract
While genetic studies have shown that under non-stressed conditions both MDM2 and MDMX are essential to maintain p53 in its latent form, the underlying molecular mechanism of how these inhibitors cooperate and regulate p53 is still unclear. To gain insight into this question, we have generated various chimeric proteins and demonstrated that MDM2 and MDMX can form a complex. In this study, by using a series of chimeric proteins between p53 and MDM2-family, we observed that MDM2/MDMX heterocomplex has the ability to ubiquitinate p53 far more efficiently than MDM2 alone. In vivo, MDM2/MDMX heterocomplexes are the predominant form versus the MDM2 homocomplexs. Disruption of the binding between MDM2 and MDMX resulted in a marked increase in both abundance and activity of p53, emphasizing the functional importance of this heterocomplex in p53 control. These results suggest that the complex formation between Ring finger domains of MDM2-family is essential for E3 ubiqutin ligase activity. It has been shown that MDMX was rapidly degraded in response to DNA damage, a phenomenon which is critical for p53 stabilization and activation. This degradation is mediated by MDM2, which via a distinct mechanism preferentially ubiquitinates MDMX ensuring optimal p53 activation. We propose that the interaction between MDM2 and MDMX represents an important mode of p53 regulation.
