Control of caspase activation in apoptosis

细胞凋亡中 caspase 激活的控制

• 批准号: 8466986
• 负责人: Sally A Kornbluth
• 金额: $ 30.97万
• 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/8466986
• 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.

描述（由申请人提供）：细胞凋亡导致的细胞死亡导致从活组织中去除单个细胞而不损害周围组织。近年来，人们认识到对细胞凋亡的抵抗是癌症的一个标志，对化疗的抵抗可能源于细胞凋亡信号传递的失败。 我们发现，癌细胞中常见的高水平葡萄糖代谢可以有效抑制细胞凋亡。特别是，我们发现，当磷酸戊糖途径 (PPP) 活性较高时，响应多种化疗药物而激活的起始 caspase 半胱天冬酶 2 (C2) 会受到抑制。我们发现 PPP 产生的丰富的 NADPH 会促进激酶 CaMKII 的激活，从而磷酸化并抑制 C2。小酸性蛋白 14-3-3 与磷酸化 C2 的结合？防止 C2 去磷酸化、二聚化和激活。相反，当葡萄糖或其他营养素缺乏时，14-3-3 ?从 C2 释放以允许去磷酸化和激活。我们最近发现 14-3-3 ？当营养物质耗尽时，乙酰化会阻碍与 C2 的结合（因此 PPP 无法运行），并且 14-3-3 ?由 Sirt1 催化的去乙酰化作用在营养充足的条件下受到刺激。 该资助的目的是 1) 描绘连接 NADPH 和 CaMKII 的分子途径，2) 确定如何调节 Sirt1 来控制 14-3-3 ?-C2 相互作用，3) 确定是否可以通过操纵连接代谢和 C2 的途径来改变乳腺癌细胞的化学反应性。