Control of caspase activation in apoptosis

细胞凋亡中 caspase 激活的控制

基本信息

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
项目类别：
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

项目摘要

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）：抑制细胞凋亡是癌症的标志之一，与细胞增殖增加一起导致肿瘤发生。细胞恶性转化后，葡萄糖代谢发生了改变，但是这些代谢变化在肿瘤发生中的重要性并不完全清楚。此外，尚不清楚如何将代谢变化与对肿瘤发生重要的凋亡抑制有关。在此提案中，我们使用生物化学功能强大的Xenopus卵/卵母细胞模型系统来检查细胞的养分状态可以调节细胞生存或死亡的倾向的假设。在初步工作中，我们已经确定了由卵母细胞/卵的代谢状态控制的信号通路，并证明五肽磷酸盐途径的NADPH产生对于这些细胞的存活至关重要。该调节的目标是凋亡蛋白酶，caspase 2。具体来说，在存在丰富的NADPH存在下抑制细胞死亡，或足够的6-磷酸葡萄糖抑制磷酸磷酸五磷酸途径的运行，这是由calcium Calspase 2通过Calcium Calmoduldentent依赖蛋白依赖蛋白依赖蛋白依赖性基因酶II（Camkiii）的抑制作用。相反，在CAMKII磷酸化位点，caspase 2在细胞死亡之前的激活（养分耗竭后）在caspase 2之前脱磷酸化。与这些观察结果一致，caspase 2的突变体变体能够通过CAMKII逃避磷酸化，可以覆盖NADPH介导的凋亡抑制。初步数据表明，胱天蛋白酶的代谢调节也有助于其他细胞类型的凋亡控制。因此，我们假设在一生中（在卵母细胞的情况下）逐渐耗尽细胞营养素或致癌过程中戊糖磷酸途径的异常操作，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。该建议的目的是了解营养利用率途径如何控制凋亡蛋白酶，caspase 2。