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: 6816324
• 负责人: BETH C LEVINE
• 金额: $ 31.98万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6816324
• 关键词: BCL2 gene /protein; Bax gene /protein; Caenorhabditis elegans; apoptosis; autophagy; biological signal transduction; cell growth regulation; enzyme activity; fluorescence resonance energy transfer; genetically modified animals; green fluorescent proteins; laboratory mouse; phosphatidylinositol 3 kinase; protein protein interaction; protein structure function; site directed mutagenesis; transfection /expression vector; yeast two hybrid system

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）：凋亡和自噬是遗传控制的细胞途径，这些途径涉及确定细胞命运，组织稳态和发育。尽管有一些有关两种途径之间分子联系的线索，但对凋亡和自噬之间的相互关系知之甚少。以前，我们确定了与Bcl-2家族的细胞抗凋亡蛋白相互作用的哺乳动物自噬蛋白Beclin 1。在这笔赠款中，我们建议探讨Beclin 1-Bcl-2家族成员相互作用的功能意义，以调节自噬和凋亡的调控以及这些相互作用在秀丽隐杆线虫和小鼠发育中的作用。在第一个特定目的中，我们将使用酵母，秀丽隐杆线虫遗传和哺乳动物系统来研究Bcl-2直系同源物抑制Beclin 1直系同源依赖性自噬的假设。我们将评估这种抑制是否需要Bcl-2直系同源物与Beclin 1直系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级III PI3K复合物相关的PI3激酶活性。在第二个特定目标中，我们将使用秀丽隐杆线虫遗传和哺乳动物系统来研究Beclin 1直系同源物主要作为BCL-2直系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直系同源物的生存作用是否需要蛋白质 - 蛋白质与Bcl-2直系同源物的相互作用，并且我们将评估Beclin 1直系同源物促进Bcl-2直系同源物的抗死活性的可能机制。 总之，这些研究将定义Bcl-2抗凋亡蛋白与Beclin 1自噬蛋白之间相互作用的功能意义。预期获得的结果有助于解读凋亡和自噬途径之间的进化保守的相互关系，并对理解正常发育和凋亡和自噬的病理生理过程具有重要意义。