"Conserved Cell Death Pathways in Mammals and Yeast"

“哺乳动物和酵母中保守的细胞死亡途径”

• 批准号: 7492396
• 负责人: J. Marie Hardwick
• 金额: $ 7.74万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7492396
• 关键词: Apoptosis; Biochemical; Bioenergetics; Biogenesis; Cancer Etiology; Cell Death; Cell Death Inhibition; Cells; Cessation of life; Complex; Condition; Eukaryota; Eukaryotic Cell; Family; Family member; Figs - dietary; Follicular Lymphoma; Gene Order; Genes; Genetic Screening; Hand; Heat-Shock Response; Herpesviridae; Homologous Gene; Human; Knock-out; Libraries; Maintenance; Malignant Neoplasms; Mammalian Cell; Mammals; Metabolic stress; Mitochondria; Modeling; Molecular; Molecular Mechanisms of Action; Morphology; Occupations; Open Reading Frames; Pathway interactions; Protein Family; Proteins; Regulation; Role; Saccharomyces cerevisiae; Simplexvirus; Stimulus; Techniques; Thinking; Translocation Breakpoint; Virus; Virus Diseases; Work; Yeasts; day; insight; nervous system disorder; plant fungi; programs; protein function; tool; tumor; yeast genetics

The association between Bcl-2 and cancer has been known for 20 years. But the biochemical mechanisms to explain why Bcl-2, found at translocation breakpoints in follicular lymphomas, why elevated Bcl-xL expression in many tumor types, and why herpesviruses that encode Bcl-2 homologues cause cancer, remains unknown. The field has focused considerable effort to understand the complex interactions between anti-death (Bcl-2 and Bcl-xL) and pro-death (Bax and Bak) family proteins, and their mechanisms of action after cells have received a stimulus that induced apoptosis. The work in our lab has forced us to think in another direction, to pursue the basic biochemical functions of Bcl-2 family proteins that function prior to receipt of a death stimulus, and that we predict are shared between both anti- and pro-death family members. These 'day-jobs' are also predicted to explain the anti-death functions of human Bcl-2 proteins in a remarkable diverisity of species including mammals, plants and fungi, Therefore, we propose to apply the new tools available for yeast to study the 'core1 functions of Bcl-2 family proteins. First, we seek to identify genes that regulate programmed cell death in yeast. Several different death stimuli, including viruses, heat shock and metabolic stress, will be applied to the complete library of yeast knockout strains under conditions that distinguish anti- and pro-death genes. Factors that are common or unique to specific pathways will be distinguished. These pathways will be ordered and candidate yeast regulators of cell death already on hand will be further investigated to determine the connection between their ability to regulate mitochondria! morphology and function. Finally, yeast will be probed to identifiy those genes that are required for human Bcl-2 and Bcl-xL to inhibit cell death in yeast. We expect that these newly unidentified yeast factors will be involved in the maintenance, biogenesis and degradation of mitochondria, and in close proximity to the regulation of bioenergetics.

BCL-2与癌症之间的关联已有20年了。但是生化机制 解释为什么Bcl-2在卵泡淋巴瘤中的易位断点中发现，为什么升高Bcl-XL 在许多肿瘤类型中的表达，以及为什么编码Bcl-2同源物引起癌症的疱疹病毒为什么 仍然未知。该领域集中了巨大的努力，以了解之间的复杂互动 抗死（Bcl-2和Bcl-XL）和亲死亡（Bax和Bak）家族蛋白及其作用机理 细胞收到诱导凋亡的刺激后。我们实验室的工作迫使我们思考 另一个方向，追求Bcl-2家族蛋白的基本生化功能 接收死亡刺激，我们预测抗死家族之间共享 成员。这些“日常工作 因此 酵母可用于研究Bcl-2家族蛋白的“ Core1功能”的新工具。首先，我们试图确定 调节酵母中编程细胞死亡的基因。几种不同的死亡刺激，包括病毒，热量 休克和代谢压力将在条件下应用于酵母敲除菌株的完整库 区分抗死基因。特定途径的常见因素或特定途径独有的因素是 区分。这些途径将被订购，候选细胞死亡的酵母调节剂 将进一步研究以确定其调节线粒体的能力之间的联系！ 形态和功能。最后，将探测酵母以鉴定人类所需的基因 Bcl-2和Bcl-XL抑制酵母细胞死亡。我们预计这些新未识别的酵母菌因素将是 参与线粒体的维持，生物发生和降解，并与 生物能学的调节。