"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）：BCL-2与癌症之间的关联已有20年了。但是，生化机制是为了解释为什么在卵泡淋巴瘤中的易位断点中发现的Bcl-2，为什么在许多肿瘤类型中升高Bcl-XL表达，以及为什么编码Bcl-2同源物引起癌症的疱疹病毒的原因尚不清楚。该领域集中了巨大的努力，以了解抗死亡（BCL-2和BCL-XL）和pro Death（Bax和Bak）家族蛋白之间的复杂相互作用，并且它们在细胞后的作用机制已收到诱导凋亡的刺激。我们实验室中的工作迫使我们朝另一个方向思考，追求在收到死亡刺激之前起作用的Bcl-2家族蛋白的基本生化功能，并且我们预测的是在抗死家族和亲死亡家族之间共享。还预测，这些“日常工作”也可以解释人类Bcl-2蛋白在包括哺乳动物，植物和真菌在内的各种物种中的抗死亡功能，因此，我们建议将可用于研究Bcl-2家族蛋白的'Core1功能的新工具应用于BCL-2家族蛋白的功能。首先，我们试图确定调节酵母中编程细胞死亡的基因。在区分抗死基因的条件下，几种不同的死亡刺激，包括病毒，热休克和代谢应激，将应用于酵母敲除菌株的完整库。将区分特定途径的常见因素或独特的因素。这些途径将被订购，并将进一步研究细胞死亡的候选酵母调节剂，以确定其调节线粒体形态和功能的能力之间的联系。最后，将探测酵母以鉴定人Bcl-2和Bcl-XL所需的那些基因，以抑制酵母中的细胞死亡。我们预计，这些新近未识别的酵母菌因子将与线粒体的维持，生物发生和降解有关，并与生物能学的调节非常接近。