SIGNAL TRANSDUCTION AND CELL DEATH REGULATION

信号转导和细胞死亡调节

• 批准号: 6260269
• 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/6260269
• 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.

Caspases 是半胱氨酸蛋白酶家族，是大多数细胞的核心 死亡计划，因此提出了一个有吸引力的治疗目标 干预措施。研究人员发现 PKC 信号转导 途径调节抗癌药物敏感性，但其机制 监管不完全了解。 PKC 分为三类 同工酶 - 传统（α、β1、β2 和 γ）、新型（δ、ε、 eta、theta 和 mu）和非典型（zeta 和 lambda / iota）。新型 PKC 同工酶 是半胱天冬酶的底物，这些同工酶的蛋白水解激活具有 与细胞死亡有关。初步研究表明PKC还可以 通过凋亡刺激影响 caspase 的激活，表明 PKC 信号转导途径可以通过细胞凋亡来增加细胞死亡 刺激。研究人员假设 PKC 不仅在下游发挥作用 半胱天冬酶的上游，也位于半胱天冬酶的上游，以调节半胱天冬酶的激活和 化疗药物引起的细胞死亡，并且催化片段和 PKC全酶决定细胞的存活和死亡。具体目标是： (1) 描述顺铂诱导的 caspase 级联反应的哪些步骤 受PKC监管； (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) 至 确定 PKC 信号转导通路的失调是否会影响 Caspase 激活和顺铂耐药。