Beclin 1 Bcl-2 Interactions: Effects on Apoptosis

描述(申请人提供)：细胞凋亡和自噬都是基因控制的细胞通路，参与决定细胞命运、组织内稳态和发育。尽管有一些关于这两条途径之间的分子联系的线索，但对于细胞凋亡和自噬之间的相互关系还知之甚少。在此之前，我们鉴定了哺乳动物的自噬蛋白Beclin 1，它与细胞中的抗凋亡蛋白Bcl2家族相互作用。在这项资助中，我们建议探索Beclin 1-Bcl2家族成员相互作用在调节自噬和凋亡方面的功能意义，以及这些相互作用在线虫和小鼠发育中的作用。在第一个特定目标中，我们将使用酵母、线虫遗传系统和哺乳动物系统来研究Bcl-2同源基因抑制Beclin 1同源基因依赖的自噬的假设。我们将评估这种抑制是否需要Bcl2同源物和Beclin 1同源物之间直接的蛋白质-蛋白质相互作用，以及其机制是否涉及破坏Beclin 1-Class III PI3K复合体相关的PI3激酶活性。在第二个特定目标中，我们将使用线虫的遗传和哺乳动物系统来研究Beclin 1同源基因主要作为生存基因发挥作用的假设，这是抗Bcl2同源基因抗凋亡功能所必需的。我们将测试Beclin 1同源基因的生存效应是否需要与Bcl2同源基因的蛋白质-蛋白质相互作用，并将评估Beclin 1基因同源基因促进Bcl2基因同源基因的抗死亡活性的可能机制。总之，这些研究将确定Bcl2抗凋亡蛋白和Beclin 1自噬蛋白之间相互作用的功能意义。这些结果有望帮助破译细胞凋亡和自噬途径之间进化上保守的相互关系，并对理解细胞凋亡和自噬发生的正常发育和病理生理过程具有重要意义。

DESCRIPTION (provided by applicant): Apoptosis and autophagy are both genetically controlled cellular pathways that are involved in determining cell fate, tissue homeostasis, and development. Despite some clues about molecular links between the two pathways, the interrelationship between apoptosis and autophagy is poorly understood. Previously, we identified the mammalian autophagy protein, Beclin 1, that interacts with cellular anti-apoptotic proteins of the Bcl-2 family. In this grant, we propose to explore the functional significance of Beclin 1-Bcl-2 family member interactions with respect to the regulation of autophagy and apoptosis and the role of these interactions in C. elegans and mouse development. In the first specific aim, we will use yeast, C. elegans genetic and mammalian systems to investigate the hypothesis that Bcl-2 orthologs inhibit Beclin 1 ortholog dependent autophagy. We will evaluate whether such inhibition requires direct protein-protein interactions between Bcl-2 orthologs and Beclin 1 orthologs and whether the mechanism involves disruption of the Beclin 1-Class III PI3K complex-associated PI3 kinase activity. In the second specific aim, we will use C. elegans genetic and mammalian systems to investigate the hypothesis that Beclin 1 orthologs function primarily as survival genes that are required for the anti-apoptotic function of Bcl-2 orthologs. We will test whether the survival effects of Beclin 1 orthologs require protein-protein interactions with Bcl-2 orthologs and we will evaluate possible mechanisms by which Beclin 1 orthologs promote anti-death activity of Bcl-2 orthologs. Together, these studies will define the functional significance of interactions between the Bcl-2 anti-apoptotic proteins and Beclin 1 autophagy proteins. The results obtained are expected to help decipher the evolutionarily conserved interrelationships between apoptosis and autophagy pathways and to have important implications for understanding the normal developmental and the pathophysiological processes in which both apoptosis and autophagy occur.