Control of caspase activation in apoptosis

细胞凋亡中 caspase 激活的控制

• 批准号: 7678370
• 负责人: Sally A Kornbluth
• 金额: $ 28.86万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-21 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7678370
• 关键词: Age; Apoptosis; Apoptotic; Biological; Biological Models; Birth; Calcium; Calmodulin; Caspase; Cell Death; Cell Death Inhibition; Cell Proliferation; Cell Survival; Cells; Cessation of life; Data; Degenerative Disorder; Embryonic Development; Excision; Female; Generations; Glucose-6-Phosphate; Goals; Immune system; Individual; Inhibition of Apoptosis; Life; Link; Malignant - descriptor; Malignant Neoplasms; Mediating; Menopause; Metabolic; Metabolic Control; Metabolism; Modeling; Molecular; Mus; NADP; Normal tissue morphology; Nutrient; Oocytes; Operative Surgical Procedures; Organism; Pathway interactions; Pentosephosphate Pathway; Peptide Hydrolases; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Production; Protein Dephosphorylation; Radiation; Regulation; Regulation of Apoptosis Pathway; Resistance; Role; Signal Pathway; Structure; Time; Tissues; Variant; Vertebrates; Woman; Work; Xenopus; carcinogenesis; caspase-2; cell transformation; cell type; egg; exhaustion; glucose metabolism; human female; injured; mutant; prevent; stressor; tumorigenesis

DESCRIPTION (provided by applicant): Inhibition of apoptosis is one of the hallmarks of cancer, which, together with increased cellular proliferation, leads to tumorigenesis. Following malignant transformation of cells, glucose metabolism is altered, but the importance of these metabolic changes in tumorigenesis is not entirely clear. Moreover, how metabolic changes may be linked to the inhibition of apoptosis important for tumorigenesis is not known. In this proposal, we use the biochemically powerful Xenopus egg/oocyte model system to examine the hypothesis that a cell's nutrient status can regulate the propensity of a cell to live or die. In preliminary work, we have identified a signaling pathway controlled by the metabolic state of the oocyte/egg and have demonstrated that generation of NADPH by the pentose phosphate pathway is critical for survival of these cells. The target of this regulation is an apoptotic protease, caspase 2. Specifically, inhibition of cell death in the presence of abundant NADPH, or sufficient glucose- 6-phosphate to drive operation of the pentose phosphate pathway, resulted from the inhibitory phosphorylation of caspase 2 by Calcium calmodulin-dependent kinase II (CaMKII). Conversely, activation of caspase 2 prior to cell death (following nutrient depletion) was preceded by dephosphorylation of caspase 2 at the CaMKII phosphorylation site. Consistent with these observations, a mutant variant of caspase 2 able to escape phosphorylation by CaMKII could override NADPH-mediated inhibition of apoptosis. Preliminary data indicate that metabolic regulation of caspases contribute to apoptotic control in other cell types as well. Thus, we hypothesize that the gradual exhaustion of cellular nutrients over the course of a lifetime (in the case of the oocyte) or aberrant operation of the pentose phosphate pathway during carcinogenesis, may result in an inability to drive the NADPH production required to suppress caspase 2, thereby contributing to cell death. The goal of this proposal is to understand how nutrient utilization pathways control the apoptotic protease, caspase 2.

描述（由申请人提供）：细胞凋亡的抑制是癌症的标志之一，它与细胞增殖的增加一起导致肿瘤发生。细胞恶性转化后，葡萄糖代谢发生改变，但这些代谢变化在肿瘤发生中的重要性尚不完全清楚。此外，代谢变化如何与对肿瘤发生重要的细胞凋亡的抑制联系起来尚不清楚。在本提案中，我们使用生化强大的爪蟾卵/卵母细胞模型系统来检验细胞的营养状态可以调节细胞生存或死亡倾向的假设。在初步工作中，我们已经确定了受卵母细胞/卵子代谢状态控制的信号通路，并证明戊糖磷酸通路产生 NADPH 对于这些细胞的生存至关重要。这种调节的目标是凋亡蛋白酶，caspase 2。具体来说，在存在丰富的 NADPH 或足够的 6-磷酸葡萄糖以驱动戊糖磷酸途径运行的情况下抑制细胞死亡，是由钙钙调蛋白依赖性激酶 II (CaMKII) 对 caspase 2 的抑制性磷酸化造成的。相反，在细胞死亡（营养耗尽后）之前激活 caspase 2，然后在 CaMKII 磷酸化位点处进行 caspase 2 去磷酸化。与这些观察结果一致，能够逃避 CaMKII 磷酸化的 caspase 2 突变体可以超越 NADPH 介导的细胞凋亡抑制。初步数据表明半胱天冬酶的代谢调节也有助于其他细胞类型的细胞凋亡控制。因此，我们假设在一生中细胞营养物质的逐渐耗尽（以卵母细胞为例）或致癌过程中戊糖磷酸途径的异常运行，可能导致无法驱动抑制 caspase 2 所需的 NADPH 产生，从而导致细胞死亡。该提案的目标是了解营养利用途径如何控制凋亡蛋白酶 Caspase 2。