Control of caspase activation in apoptosis

细胞凋亡中 caspase 激活的控制

基本信息

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
项目类别：
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

项目摘要

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）：细胞凋亡的细胞死亡导致从活组织中间去除单个细胞，而不会损害周围组织。近年来，人们已经认识到，对凋亡的抗性是癌症的标志，并且对化学疗法的耐药性可能源于凋亡信号传播的失败。我们发现，高水平的葡萄糖代谢，正如癌细胞中通常看到的，可以有效抑制细胞凋亡。特别是，我们发现，当响应多种化学治疗剂而激活的引发液caspase 2（C2）被抑制时，当戊糖磷酸途径（PPP）活性很高时。我们发现，由PPP产生的丰富NADPH促进了激酶CAMKII的激活以磷酸化和抑制C2。小酸性蛋白14-3-3的磷酸化C2结合？防止C2去磷酸化，二聚化和激活。相反，当葡萄糖或其他养分稀缺时，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？当养分耗尽时，乙酰化阻碍了与C2的结合（使PPP无法工作），而该营养素是14-3-3？在养分充气条件下刺激SIRTUIN SIRT1催化的脱乙酰化。该赠款的目的是1）描述连接NADPH和CAMKII的分子途径，2）确定如何调节SIRT1以控制14-3-3？-C2相互作用和3），以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措施。