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）： 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，但对凋亡和自噬之间的相互关系知之甚少。此前我们 确定了哺乳动物自噬蛋白Beclin 1，它与细胞抗凋亡蛋白相互作用， Bcl-2家族本研究拟探讨Beclin 1-Bcl-2家族在肿瘤细胞中的功能意义 成员之间的相互作用方面的调节自噬和凋亡，以及这些作用， C.相互作用elegans和小鼠发育。在第一个具体目标中，我们将使用酵母，C。elegans 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直系同源物和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Beclin 1直系同源物的破坏。 1-III类PI 3 K复合物相关的PI 3激酶活性。在第二个具体目标中，我们将使用C。elegans 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直系同源物的抗凋亡功能所需的存活基因。我们将测试 Beclin 1直系同源物的存活效应需要与Bcl-2直系同源物的蛋白质-蛋白质相互作用， 评估Beclin 1直系同源物促进Bcl-2直系同源物抗死亡活性的可能机制。 总之，这些研究将确定Bcl-2抗凋亡蛋白与凋亡抑制蛋白之间相互作用的功能意义。 Beclin 1自噬蛋白。所获得的结果有望帮助破译 细胞凋亡和自噬途径之间进化上保守的相互关系， 对理解正常发育和病理生理过程的重要意义， 细胞凋亡和自噬都会发生。