"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: 7993612
• 负责人: J. Marie Hardwick
• 金额: $ 6.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-20 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7993612
• 关键词: Apoptosis; Biochemical; Bioenergetics; Biogenesis; Cancer Etiology; Cell Death; Cell Death Inhibition; Cells; Cessation of life; Complex; Eukaryota; 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; Translocation Breakpoint; Virus; Virus Diseases; Work; Yeasts; 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为人所知 20 年。但解释为什么在滤泡性淋巴瘤易位断点处发现的 Bcl-2、为什么在许多肿瘤类型中 Bcl-xL 表达升高以及为什么编码 Bcl-2 同源物的疱疹病毒会导致癌症的生化机制仍然未知。该领域投入了大量精力来了解抗死亡（Bcl-2 和 Bcl-xL）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从另一个方向思考，追寻 Bcl-2 家族蛋白的基本生化功能，这些蛋白在收到死亡刺激之前发挥作用，并且我们预测，抗死亡和亲死亡家族成员都具有这种功能。这些“日常工作”预计也能解释人类 Bcl-2 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 Bcl-2 家族蛋白的“核心 1 功能”。首先，我们寻求鉴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，将在区分抗死亡基因和促死亡基因的条件下应用于完整的酵母敲除菌株文库。将区分特定途径的共同或独特因素。这些途径将被排序，并且现有的候选酵母细胞死亡调节剂将被进一步研究，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，将探测酵母以确定人类 Bcl-2 和 Bcl-xL 抑制酵母细胞死亡所需的基因。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，并与生物能学的调节密切相关。

项目成果

Comment on "Sterilizing immunity in the lung relies on targeting fungal apoptosis-like programmed cell death".

• DOI: 10.1126/science.aar6910
• 发表时间: 2018-06-22
• 期刊: Science (New York, N.Y.)
• 作者: Aouacheria A;Cunningham KW;Hardwick JM;Palková Z;Powers T;Severin FF;Váchová L
• 通讯作者: Váchová L

Whi2: a new player in amino acid sensing.

Whi2：氨基酸传感领域的新玩家。

• DOI: 10.1007/s00294-018-00929-9
• 发表时间: 2019
• 期刊: Current genetics
• 影响因子: 2.5
• 作者: Teng,Xinchen;Hardwick,JMarie
• 通讯作者: Hardwick,JMarie

Do Fungi Undergo Apoptosis-Like Programmed Cell Death?

• DOI: 10.1128/mbio.00948-18
• 发表时间: 2018-07-01
• 期刊: MBIO
• 影响因子: 6.4
• 作者: Hardwick, J. Marie

Whi2 is a conserved negative regulator of TORC1 in response to low amino acids.

Whi2 是 TORC1 响应低氨基酸的保守负调节因子。

• DOI: 10.1371/journal.pgen.1007592
• 发表时间: 2018-08
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Chen X;Wang G;Zhang Y;Dayhoff-Brannigan M;Diny NL;Zhao M;He G;Sing CN;Metz KA;Stolp ZD;Aouacheria A;Cheng WC;Hardwick JM;Teng X
• 通讯作者: Teng X

Whi2 signals low leucine availability to halt yeast growth and cell death.

• DOI: 10.1093/femsyr/foy095
• 发表时间: 2018-08
• 期刊: FEMS yeast research
• 影响因子: 3.2
• 作者: Xinchen Teng;Xinchen Teng;Xinchen Teng;E. Yau;Cierra N. Sing;J. M. Hardwick;J. M. Hardwick