"Conserved Cell Death Pathways in Mammals and Yeast"

Bcl-2与癌症之间的关系已经被发现了20年。但生物化学机制 为了解释为什么在滤泡性淋巴瘤的易位断点发现Bcl-2，为什么Bcl-xL升高， 在许多肿瘤类型中的表达，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。该领域已经集中了相当大的努力，以了解复杂的相互作用， 抗死亡（Bcl-2和Bcl-xL）和促死亡（Bax和巴克）家族蛋白及其作用机制 在细胞接受了诱导凋亡的刺激之后。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，这些蛋白在 死亡刺激的接收，我们预测在反对和赞成死亡的家庭之间是共享的 成员这些“日常工作”也被预测可以解释人类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的显著多样性，因此，我们建议将 酵母研究Bcl-2家族蛋白质核心功能的新工具。首先，我们要确定 控制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，将被施加到酵母敲除菌株的条件下， 来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 杰出的这些途径将有序和候选酵母调节细胞死亡已经在手 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，将对酵母进行探测以识别人类所需的那些基因 Bcl-2和Bcl-xL抑制酵母细胞死亡。我们希望这些新发现的酵母因子 参与线粒体的维持、生物发生和降解，并与线粒体的 生物能量学的调节。

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.