Molecular Basis of p53-Induction to DNA Damage

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DESCRIPTION (provided by applicant): Molecular Basis of p53-induction to DNA Damage Essential to p53 activation is to abrogate the ability of MDM2 to target p53 for inactivation. Despite extensive information, many important aspects regarding MDM2-mediated p53 degradation and its regulation remain not fully understood, which is in large part attributable to the complexity of the process that is regulated by a wide array of signaling pathways. Our previous study identified the residues 92-112 of p53 as an important sequence affecting p53 stability. Further experiments uncovered CRP2 as one of the proteins bond to the p53 sequence. Significantly, a role for CRP2 in the regulation of p53 stability was suggested by our preliminary study and is also supported by published reports. Other work from our laboratory identified the acidic domain of MDM2 as another region, in addition to the ring finger domain, essential for MDM2 to target p53 for full ubiquitination. However, how the acidic domain contributes to MDM2-mediated p53 degradation remains unclear. Recent genetic studies have demonstrated both MDM2 and MDMX as essential negative regulators of p53 it is unknown, however, why neither mdm2 nor mdmx can compensate for the loss of the other. The mutual functional dependency between MDM2 and MDMX, as demonstrated by our recent studies, suggests that the MDM2/MDMX heterocomplex may function as an integral unit in targeting p53 for degradation. By choosing the p53-MDM2/MDMX module as the focal point of the investigation, we propose to extend our previous studies to three specific aims for elucidating the mechanisms underlying MDM2- mediated p53 degradation and the p53 response to stress. The specific aims are: 1. Assess CRP2, a protein that binds to the residues 92-112 of p53, for its role in Mdm2-targeted p53 ubiquitination/degradation and the p53 response to stress. 2. Investigate a role for the MDM2 acidic domain in p53 ubiquitination/degradation. 3. Functionally characterize the MDM2/MDMX heterocomplex in p53 regulation.