Beclin 1 Bcl-2 Interactions: Effects on Apoptosis

描述（由申请人提供）：细胞凋亡和自噬都是基因控制的细胞途径，参与决定细胞命运、组织稳态和发育。尽管两种途径之间的分子联系有一些线索，但凋亡和自噬之间的相互关系尚不清楚。之前，我们发现了哺乳动物自噬蛋白Beclin 1，它与Bcl-2家族的细胞抗凋亡蛋白相互作用。在本次资助中，我们拟探索Beclin 1-Bcl-2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秀丽隐杆线虫和小鼠发育中的作用。在第一个具体目标中，我们将利用酵母、秀丽隐杆线虫的遗传系统和哺乳动物系统来研究Bcl-2同源物抑制Beclin 1同源物依赖性自噬的假设。我们将评估这种抑制是否需要Bcl-2同源物和Beclin 1同源物之间的直接蛋白-蛋白相互作用，以及其机制是否涉及Beclin 1- III类PI3K复合物相关PI3激酶活性的破坏。在第二个特定目标中，我们将使用秀丽隐杆线虫的遗传和哺乳动物系统来研究Beclin 1同源物主要作为Bcl-2同源物抗凋亡功能所需的生存基因的假设。我们将测试Beclin 1同源物的生存效应是否需要与Bcl-2同源物的蛋白-蛋白相互作用，我们将评估Beclin 1同源物促进Bcl-2同源物抗死亡活性的可能机制。总之，这些研究将明确Bcl-2抗凋亡蛋白和Beclin - 1自噬蛋白之间相互作用的功能意义。该研究结果有望帮助解释细胞凋亡和自噬途径之间的进化保守相互关系，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.