Control of caspase activation in apoptosis

细胞凋亡中 caspase 激活的控制

• 批准号: 8298331
• 负责人: Sally A Kornbluth
• 金额: $ 32.09万
• 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 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8298331
• 关键词: Acetylation; Age; Apoptosis; Apoptotic; Binding; Birth; Breast Cancer Cell; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calmodulin; Caspase; Cell Death; Cell Survival; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; Data; Deacetylase; Deacetylation; Development; Dimerization; Environment; Excision; Failure; Female; Glucose; Glucose-6-Phosphate; Goals; Grant; Immune system; Individual; Life; Link; Longevity; Malignant Neoplasms; Menopause; Metabolic; Metabolism; Modeling; Molecular; Mus; NADP; Nutrient; Oocytes; Pathway interactions; Pentosephosphate Pathway; Peptide Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Play; Predisposition; Protein Dephosphorylation; Protein phosphatase; Proteins; Radiation; Resistance; Role; Signal Transduction; Site; Somatic Cell; Therapeutic; Time; Tissues; Vertebrates; Woman; Work; Xenopus oocyte; cancer cell; cancer therapy; caspase-2; cell injury; cell suicide; chemotherapeutic agent; chemotherapy; glucose metabolism; human female; insight; prevent; pro-caspase-2; programs; response; stem; stressor; transmission process

DESCRIPTION (provided by applicant): Cell death by apoptosis results in the removal of individual cells from the midst of a living tissue without damage to surrounding tissue. In recent years, it has been recognized that resistance to apoptosis is a hallmark of cancers and that resistance to chemotherapy can stem from a failure in apoptotic signal transmission. We have found that high levels of glucose metabolism, as is typically seen in cancer cells, can potently suppress apoptosis. In particular, we have found that the initiator caspase, caspase 2 (C2), activated in response to a number of chemotherapeutic agents, is suppressed when pentose phosphate pathway (PPP) activity is high. We have found that abundant NADPH, produced by the PPP, promotes activation of the kinase CaMKII to phosphorylate and suppress C2. Binding of phosphorylated C2 by the small acidic protein 14-3-3? prevents C2 dephosphorylation, dimerization, and activation. Conversely, when glucose or other nutrients are scarce, 14-3-3 ? is released from C2 to allow dephosphorylation and activation. We have recently found that 14- 3-3 ? binding to C2 is impeded by acetylation when nutrients are depleted (so that the PPP cannot operate) and that 14-3-3 ? deacetylation, catalyzed by the sirtuin, Sirt1, is stimulated under nutrient replete conditions. The aims of this grant are 1) to delineate the molecular pathways linking NADPH and CaMKII, 2) to determine how Sirt1 is regulated to control 14-3-3 ?-C2 interactions and 3) to determine whether chemoresponsiveness of breast cancer cells can be altered by manipulating the pathways linking metabolism and C2. PUBLIC HEALTH RELEVANCE: The goal of this grant is to determine how metabolism regulates the apoptotic protease, caspase 2 and to determine how metabolic manipulation might be used to enhance caspase-2 activation. As caspase 2 has been implicated in the response to some chemotherapeutic agents, this work may provide avenues for enhancing the response to cancer chemotherapy.

描述（由申请人提供）：细胞凋亡导致的细胞死亡导致单个细胞从活组织中移出，而不损伤周围组织。近年来，人们已经认识到，对细胞凋亡的抗性是癌症的标志，并且对化疗的抗性可能源于细胞凋亡信号传递的失败。 我们已经发现，高水平的葡萄糖代谢，通常在癌细胞中看到，可以有效地抑制细胞凋亡。特别是，我们已经发现，当戊糖磷酸途径（PPP）活性高时，响应于许多化疗剂而激活的引发剂胱天蛋白酶，胱天蛋白酶2（C2）被抑制。我们已经发现，丰富的NADPH，产生的PPP，促进激活的激酶CaMKII磷酸化和抑制C2。磷酸化C2的小酸性蛋白14-3-3的结合？阻止C2去磷酸化、二聚化和活化。相反，当葡萄糖或其他营养素缺乏时，14-3-3？从C2中释放，使其去磷酸化和活化。我们最近发现14- 3-3？结合到C2是阻碍乙酰化时，营养素耗尽（使PPP无法运作）和14-3-3？由sirtuin，Sirt 1催化的脱乙酰化在营养物充足的条件下被刺激。 这项资助的目的是1）描绘连接NADPH和CaMKII的分子途径，2）确定Sirt 1是如何调节以控制14-3-3？- C2相互作用和3）确定乳腺癌细胞的化学反应性是否可以通过操纵连接代谢和C2的途径来改变。 公共卫生相关性： 这项资助的目标是确定代谢如何调节凋亡蛋白酶caspase-2，并确定如何代谢操纵可能被用来增强caspase-2的激活。由于半胱天冬酶2参与了对某些化疗药物的反应，这项工作可能为增强对癌症化疗的反应提供途径。