p53 and Apoptosis: The Mitochondrial Pathway

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DESCRIPTION (provided by applicant): The inactivation of the p53 pathway occurs frequently in tumors and is associated with the resistance of tumor cells towards apoptosis. We recently found that a common p53 polymorphic variant R72 (instead of P72) has enhanced binding to its negative regulator MDM2, ubiquitination, nuclear export, mitochondrial localization, and apoptosis. We found that mitochondrial p53 binds directly to the death effector BAK, leading to disruption of BAK-MCL1 interaction and induction of BAK oligomerization and cytochrome c release. The p53-mediated cytochrome c release is dependent on BAK, since it fails to occur in mitochondria from BAK-deficient cells. The goals of this proposal are to provide an added understanding of the contribution of mitochondrial p53 to apoptosis induction, so that more effective anti-tumor therapies might be developed. The specific aims include the following: (1) to define the minimal p53 domain sufficient for BAK binding and activation, with the intent to create a mini-p53 protein or a peptide-mimetic exhibiting similar properties when introduced into tumor cells; (2) to define the contribution of ubiquitination to p53 mitochondrial localization and apoptosis induction, to provide a mechanistic basis for targeting the p53 pathway in tumors.