"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为人所知 20 年。但生化机制 解释为什么在滤泡性淋巴瘤易位断点处发现 Bcl-2，为什么 Bcl-xL 升高 在许多肿瘤类型中表达，以及为什么编码 Bcl-2 同源物的疱疹病毒会导致癌症， 仍然未知。该领域投入了大量精力来理解之间复杂的相互作用 抗死亡（Bcl-2 和 Bcl-xL）和促死亡（Bax 和 Bak）家族蛋白及其作用机制 当细胞受到诱导细胞凋亡的刺激后。我们实验室的工作迫使我们思考 另一个方向是探究 Bcl-2 家族蛋白的基本生化功能，这些蛋白先于 Bcl-2 家族蛋白发挥作用。 接受死亡刺激，并且我们预测反对死亡和支持死亡的家庭都会共享这种刺激 成员。这些“日常工作”预计也能解释人类 Bcl-2 蛋白的抗死亡功能 包括哺乳动物、植物和真菌在内的物种具有显着的多样性，因此，我们建议应用 酵母可利用新工具来研究 Bcl-2 家族蛋白的“核心 1 功能”。首先，我们试图确定 调节酵母程序性细胞死亡的基因。几种不同的死亡刺激，包括病毒、热 休克和代谢应激，将在条件下应用于完整的酵母敲除菌株文库 区分抗死亡基因和促死亡基因。特定途径的共同或独特因素将是 杰出的。这些途径将被订购，细胞死亡的候选酵母调节剂已经存在 将进一步研究以确定它们调节线粒体的能力之间的联系！ 形态和功能。最后，将探测酵母以确定人类所需的基因 Bcl-2 和 Bcl-xL 抑制酵母细胞死亡。我们预计这些新发现的酵母因子将被 参与线粒体的维持、生物发生和降解，并且与线粒体密切相关 生物能量学的调节。