p53 and Apoptosis: The Mitochondrial Pathway

p53 和细胞凋亡：线粒体途径

• 批准号: 6880656
• 负责人: JULIA I LEU
• 金额: $ 4.99万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-11 至 2007-02-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6880656
• 关键词: p53; Apoptosis; Mitochondrial; Pathway

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.

描述（由申请人提供）：p53通路的失活经常发生在肿瘤中，并且与肿瘤细胞对凋亡的抗性有关。我们最近发现，一种常见的p53多态性变体R72（而不是P72）增强了与其负调节因子MDM 2的结合，泛素化，核输出，线粒体定位和凋亡。我们发现，线粒体p53直接结合到死亡效应巴克，导致BAK-MCL 1相互作用的破坏和诱导巴克寡聚化和细胞色素c释放。p53介导的细胞色素c释放依赖于巴克，因为它不能发生在BAK缺陷细胞的线粒体中。该提案的目标是提供线粒体p53对细胞凋亡诱导的贡献的额外理解，以便开发更有效的抗肿瘤疗法。（1）确定足以结合和激活巴克的最小p53结构域，目的是产生当引入肿瘤细胞时表现出类似性质的mini-p53蛋白或肽模拟物;（2）确定泛素化对p53线粒体定位和凋亡诱导的作用，为靶向肿瘤中的p53通路提供机制基础。