"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: 7415174
• 负责人: J. Marie Hardwick
• 金额: $ 30.26万
• 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/7415174
• 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; Stimulus; Techniques; Thinking; Translocation Breakpoint; Virus; Virus Diseases; Work; Yeasts; day; insight; nervous system disorder; plant fungi; programs; protein function; tool; tumor; yeast genetics

DESCRIPTION (provided by applicant): 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 herpes viruses 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 diversity 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 identify 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.

描述(由申请人提供)：20年来，人们已经知道Bcl-2与癌症之间的联系。但是，为什么在滤泡性淋巴瘤中发现易位断裂点的Bcl-2，为什么在许多肿瘤类型中Bcl-xl表达增加，以及为什么编码Bcl-2同源物的疱疹病毒导致癌症，其生化机制仍不清楚。该领域致力于了解抗死亡(Bcl2和Bclxl)和促死亡(Bax和Bak)家族蛋白之间的复杂相互作用，以及它们在细胞受到诱导凋亡的刺激后的作用机制。我们实验室的工作迫使我们转向另一个方向，追求在收到死亡刺激之前发挥作用的Bcl-2家族蛋白的基本生化功能，我们预测这些蛋白在反死亡和支持死亡的家庭成员之间都有共同的功能。这些“日常工作”也被预测用来解释人类Bcl2蛋白在包括哺乳动物、植物和真菌在内的多种物种中的抗死亡功能，因此，我们建议应用酵母可用的新工具来研究Bcl2家族蛋白的‘核心功能’。首先，我们试图确定调控酵母细胞程序性死亡的基因。几种不同的死亡刺激，包括病毒、热休克和代谢应激，将在区分抗死亡和促死亡基因的条件下应用于酵母基因敲除菌株的完整文库。特定途径共有或独特的因素将被区分开来。这些途径将是有序的，手头已经存在的候选酵母细胞死亡调节器将被进一步研究，以确定它们调节线粒体形态和功能的能力之间的联系。最后，将对酵母进行探索，以确定人类抑制酵母中细胞死亡所需的那些基因。我们预计，这些新发现的酵母因子将参与线粒体的维持、生物发生和降解，并与生物能量学的调节密切相关。