SIGNAL TRANSDUCTION AND CELL DEATH REGULATION

信号转导和细胞死亡调节

• 批准号: 6626754
• 负责人: Alakananda Basu
• 金额: $ 20.54万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6626754
• 关键词: BCL2 gene /protein; HeLa cells; apoptosis; biological signal transduction; cis platinum compound; cysteine endopeptidases; cytochrome c; enzyme activity; isozymes; mitochondria; neoplasm /cancer pharmacology; protease inhibitor; protein kinase C; serine proteinases; site directed mutagenesis

Caspases, a family of cysteine proteases, are central to most cell death programs and therefore present an attractive target for therapeutic interventions. The investigators have shown that the PKC signal transduction pathway regulates anticancer drug sensitivity although the mechanism of regulation is incompletely understood. There are three classes of PKC isozymes-conventional (alpha, beta1, beta2 and gamma), novel (delta, epsilon, eta, theta and mu) and atypical (zeta and lambda / iota). Novel PKC isozymes are substrates for caspases and proteolytic activation of these isozymes has been linked to cell death. The preliminary study showed that PKC can also influence activation of caspases by apoptotic stimuli, suggesting that the PKC signal transduction pathway can be targeted to increase cell death by apoptotic stimuli. The investigators hypothesize that PKC functions not only downstream of caspases but also upstream of caspases to regulate caspase activation and cell death by chemotherapeutic drugs and that both the catalytic fragment and holoenzyme of PKC decide cell survival and cell death. The Specific Aims are: (1) to delineate which steps of the cisplatin-induced caspase cascade are regulated by PKC; (2) to determine the functional significance of PKC activation and down-regulation on cisplatin-induced cell death and; (3) to establish whether deregulation in the PKC signal transduction pathway affects caspase activation and cisplatin resistance.

胱天蛋白酶是半胱氨酸蛋白酶的家族，对于大多数细胞都是核心 死亡计划，因此提出了治疗的有吸引力的目标 干预措施。研究人员表明PKC信号转导 途径调节抗癌药物敏感性，尽管机制 监管尚不完全理解。有三类PKC 同工酶常规（Alpha，Beta1，Beta2和Gamma），新颖（Delta，Epsilon， ETA，Theta和Mu）和非典型（Zeta和Lambda / iota）。新型PKC同工酶 是胱天蛋白酶的底物，这些同工酶的蛋白水解激活 与细胞死亡有关。初步研究表明，PKC也可以 通过凋亡刺激影响胱天蛋白酶的激活，表明PKC 信号转导途径可以靶向以增加凋亡的细胞死亡 刺激。研究人员假设PKC不仅在下游功能 胱天蛋白酶的和胱天蛋白酶的上游，以调节caspase激活和 化学治疗药物的细胞死亡以及催化片段和 PKC的全酶决定细胞存活和细胞死亡。具体目的是： （1）描述顺铂诱导的caspase级联的哪个步骤是 由PKC调节； （2）确定PKC的功能意义 顺铂诱导的细胞死亡的激活和下调； （3）到 确定在PKC信号转导途径中是否会影响放松管制会影响 胱天冬酶激活和顺铂耐药性。