Characterization of a novel stress-regulated anti-apoptotic ubiquitin ligase

新型应激调节抗凋亡泛素连接酶的表征

• 批准号: 7567486
• 负责人: M. SAEED SHEIKH
• 金额: $ 19.63万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7567486
• 关键词: Alkalies; Apoptosis; Apoptotic; BH3 Domain; Bax protein; C-terminal; Cardiovascular system; Cell Fractionation; Cells; Cellular Stress Response; Complex; Cytoplasm; Cytosol; DNA Damage; Defect; Diabetes Mellitus; Etoposide; Family member; Genes; Homeostasis; Immunoelectron Microscopy; Inner mitochondrial membrane; Integral Membrane Protein; Malignant Neoplasms; Mediating; Membrane; Mitochondria; Molecular; Names; Neurodegenerative Disorders; Outcome Study; Outer Mitochondrial Membrane; Pathway interactions; Proteins; RNA Interference; Resistance; Stress; Tail; Testing; Toxicology; base; human disease; insight; novel; pro-apoptotic protein; protein function; public health relevance; response; ubiquitin ligase; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Although cellular responses to genotoxic (DNA damage) or ER stress are complex, they are vital for cellular homeostasis. Aberrations in cellular responses to these stresses can have profound effects giving rise to major abnormalities including cancer, cardiovascular anomalies, diabetes and neurodegenerative disorders. This application is to characterize a novel gene that we have named BBEL1 (Bax and Bak interacting E3 Ligase 1). BBEL1 encodes a novel stress-regulated E3 ubiquitin ligase that localizes to mitochondria. BBEL1 inhibits DNA damage-induced apoptosis and interacts with the pro-apoptotic Bax and Bak. We hypothesize that BBEL1 is a novel mitochondrial anti-apoptotic E3 ubiquitin ligase that mediates its anti-apoptotic effects by inhibiting Bax and Bak and thus, a key component in the cellular stress response pathways. We are proposing three specific aims to further characterize BBEL1. Specific Aim 1 is to determine the topology and localization of BBEL1. Specific Aim 2 is to investigate the molecular basis for Bax and Bak interactions with BBEL1. Specific Aim 3 is to perform structural functional characterization of BBEL1. Proposed studies are critical initial steps to characterize BBEL1 and to lay the groundwork for further in-depth studies aiming to determine the exact function of this novel ubiquitin ligase particularly in context to toxicology and pathobiology of human diseases. PUBLIC HEALTH RELEVANCE: Cellular responses to DNA damage and other types of stresses are complex yet very vital for cellular wellbeing. Defects in cellular responses to these stresses can have profound effects giving rise to major abnormalities including cancer, cardiovascular anomalies, diabetes and neurodegenerative disorders. Here we propose to characterize a novel gene BBEL1 that encodes a novel stress-regulated E3 ubiquitin ligase. BBEL1 appears to be a key component of cellular stress response pathways as it inhibits DNA damage-induced apoptosis and interacts with pro-apoptotic proteins. Proposed studies are critical initial steps to characterize BBEL1 and to lay the groundwork for further in-depth studies aiming to determine the exact function of this novel ubiquitin ligase particularly in context to toxicology and pathobiology of human diseases.

描述（由申请人提供）：虽然细胞对基因毒性（DNA 损伤）或 ER 应激的反应很复杂，但它们对于细胞稳态至关重要。细胞对这些压力的反应异常可能会产生深远的影响，导致重大异常，包括癌症、心血管异常、糖尿病和神经退行性疾病。此应用旨在表征我们命名为 BBEL1（Bax 和 Bak 相互作用的 E3 连接酶 1）的新基因。 BBEL1 编码一种定位于线粒体的新型应激调节 E3 泛素连接酶。 BBEL1 抑制 DNA 损伤诱导的细胞凋亡，并与促细胞凋亡的 Bax 和 Bak 相互作用。我们假设 BBEL1 是一种新型线粒体抗凋亡 E3 泛素连接酶，通过抑制 Bax 和 Bak 介导其抗凋亡作用，因此是细胞应激反应途径的关键组成部分。我们提出三个具体目标来进一步表征 BBEL1。具体目标 1 是确定 BBEL1 的拓扑和定位。具体目标 2 是研究 Bax 和 Bak 与 BBEL1 相互作用的分子基础。具体目标 3 是进行 BBEL1 的结构功能表征。拟议的研究是表征 BBEL1 的关键初步步骤，并为进一步深入研究奠定基础，旨在确定这种新型泛素连接酶的确切功能，特别是在人类疾病的毒理学和病理学方面。公共卫生相关性：细胞对 DNA 损伤和其他类型压力的反应很复杂，但对细胞健康至关重要。细胞对这些压力的反应缺陷可能会产生深远的影响，导致重大异常，包括癌症、心血管异常、糖尿病和神经退行性疾病。在这里，我们建议表征一个新基因 BBEL1，它编码一种新型应激调节 E3 泛素连接酶。 BBEL1 似乎是细胞应激反应途径的关键组成部分，因为它抑制 DNA 损伤诱导的细胞凋亡并与促凋亡蛋白相互作用。拟议的研究是表征 BBEL1 的关键初步步骤，并为进一步深入研究奠定基础，旨在确定这种新型泛素连接酶的确切功能，特别是在人类疾病的毒理学和病理学方面。