Beclin 1 Bcl-2 Interactions: Effects on Apoptosis

Beclin 1 Bcl-2 相互作用：对细胞凋亡的影响

• 批准号: 7448551
• 负责人: BETH C LEVINE
• 金额: $ 30.32万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7448551
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Apoptosis; Apoptotic; Autophagocytosis; BH3 Domain; Binding; Biological Process; Caenorhabditis elegans; Cell Survival; Cells; Cessation of life; Class; Complex; Data; Development; Disruption; Family; Family member; Genes; Genetic; Grant; Homeostasis; Host Defense; In Vitro; Induction of Apoptosis; Laboratories; Link; Mammalian Genetics; Maps; Mediating; Molecular; Mus; Orthologous Gene; Pathway interactions; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Process; Protein Overexpression; Proteins; Regulation; Role; Starvation; System; Testing; Tissues; Yeasts; antimicrobial; cell killing; genetic regulatory protein; insight; mitochondrial membrane; mouse model; mutant; protein function; protein protein interaction; research study; tumorigenesis

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.

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。尽管有一些关于这两种途径之间分子联系的线索，但细胞凋亡和自噬之间的相互关系仍知之甚少。此前，我们鉴定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。在这笔资助中，我们建议探索 Beclin 1-Bcl-2 家族成员相互作用在自噬和细胞凋亡调节方面的功能意义，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，我们将使用酵母、线虫遗传和哺乳动物系统来研究 Bcl-2 直向同源物抑制 Beclin 1 直向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 直向同源物和 Beclin 1 直向同源物之间的直接蛋白质-蛋白质相互作用，以及该机制是否涉及破坏 Beclin 1-Class III PI3K 复合物相关 PI3 激酶活性。在第二个具体目标中，我们将使用线虫遗传和哺乳动物系统来研究以下假设：Beclin 1 直向同源物主要作为 Bcl-2 直向同源物的抗凋亡功能所需的生存基因发挥作用。我们将测试 Beclin 1 直向同源物的生存效应是否需要与 Bcl-2 直向同源物进行蛋白质-蛋白质相互作用，并且我们将评估 Beclin 1 直向同源物促进 Bcl-2 直向同源物的抗死亡活性的可能机制。 这些研究将共同​​确定 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。所获得的结果预计将有助于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。