The p53 tumor suppressor protein is a key cellular regulatory component implicated in the control of cell growth and death. An essential determinant in the ability of p53 to mediate its multiple functions lies in it stability. The applicant has studied mechanisms underlying the regulation of p53 stability. Preliminary results show that in nonstressed cells p53 ubiquitinaton and degradation is regulated by its associated kinase, Jun-NH2 kinase (JNK), in an mdm2 independent manner. This finding provides the foundation for the applicants' hypothesis that JNK targeting of p53 ubiquitinations and degradation is central to p53 stability. To test this hypothesis the applicant proposes to: (1) identify which of the JNK isozymes is involved in the regulation of p53 stability; (2) determine the role of JNK in HPV16-E6- dependent ubiquitination and degradation of p53; (3) find which of p53- stabilitzing agents/stimuli affect JNK in the regulation of p53 stability; (4) elucidate the contribution of post-translational modifications by phosphorylation and acetylation of p53 to JNK targeting of its stability; and (5) identify domains of JNK that mediate its regulation of p53 stability. The proposed studies will be performed using novel in vitro ubiquitination and in vitro degradation assays and will be confirmed via respective in vivo assays. Successful completion of the proposed studies will provide substantial new knowledge as per the mechanisms underlying the regulation of p53 stability and possible means for altering the stability of this important tumor suppressor protein.
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