MDM2 and its homolog MDMX are both important binding partners and regulators of the p53 tumor suppressor. MDM2 is a p53-inducible ubiquitin E3 ligase that promotes p53 degradation, forming a negative feedback loop. The importance of MDM2 in regulating p53 stress response is well established. However, little is known about the regulation of MDMX and its role in signaling to p53. Knockout experiments showed that MDMX is essential for viability of wild type but not p53-null mouse embryos, indicating that it is an important inhibitor of p53. Therefore, signaling pathways to p53 are likely to target MDMX in order to achieve efficient control of p53. We recently found that DNA damage induces proteasome-mediated degradation of MDMX. MDM2 promotes ubiquitination and degradation of MDMX, suggesting that MDMX is regulated in part by MDM2. We have also identified casein kinase 1 alpha as an MDMX binding partner that enhances the ability of MDMX to inhibit p53. MDMX is often overexpressed in tumor cells containing wild type p53 through increased promoter activity. We hypothesize that signaling to p53 is in part mediated through regulation of MDMX at the level of ubiquitination, phosphorylation and transcription. We propose the following experiments to study the function and regulation of MDMX. (1) Determine the mechanism of p53 inhibition by MDMX. (2) Investigate the regulation of MDMX by ubiquitination and sumoylation. (3) Investigate the regulation of MDMX by phosphorylation. (4) Determine the mechanism of MDMX overexpression in tumor cells. These experiments should lead to a better understanding of the mechanisms that regulate MDMX and the role of MDMX in the p53 tumor suppressor pathway.
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