P53S DIRECT ROLE IN MITOCHONDRIAL CONTROL OF APOPTOSIS

描述：(改编自调查人员的摘要) P53介导的细胞凋亡机制尚不清楚。 目前的证据表明，P53通过分离的方式诱导细胞死亡 转录依赖和非依赖途径。线粒体 参与是大多数形式的细胞死亡的关键。数据来自 研究人员的实验室表明，在具有完整P53的细胞中- 介导的凋亡途径中，P53蛋白物理上存在于 线粒体与mt-hsp70的特定低丰度蛋白复合体。 MT-HSP70可能参与了线粒体的输入和p53的重折叠。这 明显的细胞器位置强烈支持直接转录- P53在肺泡癌线粒体期的独立调控作用 细胞凋亡。相比之下，神经母细胞瘤细胞对 在测试的条件下，细胞凋亡似乎含有异常高的含量 线粒体P53/mt-HSP70复合体(解除调控)水平，相关 与P53的共价修饰。这暗示着改变了 可能导致线粒体抗凋亡表型的P53 在这个肿瘤中的水平。生物化学和基因实验解决了 大鼠线粒体中P53‘S表达的功能意义 生理条件是这项提议的核心。

DESCRIPTION: (adapted from the investigator's abstract) The mechanism of p53-mediated apoptosis remains poorly understood. Current evidence suggests that p53 induces cell death by separate transcription-dependent and -independent pathways. Mitochondrial involvement is critical for most forms of cell death. Data from the investigator's laboratory suggests that in cells with an intact p53- mediated apoptotic pathway, p53 protein is physically present within the mitochondria in a specific low-abundance protein complex with mt-hsp 70. Mt-hsp70 likely mediates mitochondrial import and refolding of p53. This apparent organellar location strongly argues for a direct transcription- independent regulatory role of p53 in the mitochondrial phase of apoptosis. In contrast, neuroblastoma cells which are resistant to apoptosis under the conditions tested, appear to contain abnormally high (deregulated) levels of mitochondrial p53/mt-hsp70 complexes, associated with covalent modification of p53. This suggests an altered function of p53 which may result in an anti-apoptotic phenotype at the mitochondrial level in this tumor. Biochemical and genetic experiments addressing the functional significance of p53's presence within mitochondria under physiological conditions are the core of this proposal.