P53S DIRECT ROLE IN MITOCHONDRIAL CONTROL OF APOPTOSIS

描述：（改编自研究者摘要） p53介导的细胞凋亡的机制仍然知之甚少。 目前的证据表明，p53诱导细胞死亡， 转录依赖性和非依赖性途径。线粒体 参与对于大多数形式的细胞死亡至关重要。的数据 研究人员的实验室表明，在具有完整p53- 介导的凋亡途径，p53蛋白是物理上存在于 线粒体与MT-HSP 70形成特定的低丰度蛋白复合物。 mt-hsp 70可能介导p53的线粒体输入和重折叠。这 明显的细胞器位置强烈支持直接转录- p53在线粒体期的独立调节作用 凋亡与此相反，神经母细胞瘤细胞， 在测试条件下的细胞凋亡，似乎含有异常高的 线粒体p53/mt-hsp 70复合物的（失调）水平， p53的共价修饰。这表明， p53可能导致线粒体的抗凋亡表型， 肿瘤的水平。生物化学和遗传学实验， 线粒体内p53的存在的功能意义 生理条件是这一建议的核心。

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.