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

描述(由申请人提供)：尽管细胞对遗传毒性(DNA损伤)或内质网压力的反应是复杂的，但它们对细胞内稳态至关重要。细胞对这些应激反应的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。这个应用是为了鉴定一个新的基因，我们将其命名为BBEL1(Bax和Bak相互作用的E3连接酶1)。BBEL1编码一种新的应激调节的E3泛素连接酶，定位于线粒体。BBEL1抑制DNA损伤诱导的细胞凋亡，并与促凋亡的Bax和Bak相互作用。我们推测BBEL1是一种新的线粒体抗凋亡E3泛素连接酶，它通过抑制Bax和Bak来介导其抗凋亡作用，因此是细胞应激反应通路中的关键成分。我们提出了三个具体目标来进一步描述BBEL1。具体目标1是确定BBEL1的拓扑和定位。具体目的2是研究BAX和BAK与BBEL1相互作用的分子基础。具体目的3是进行BBEL1的结构功能表征。拟议的研究是表征BBEL1的关键的初步步骤，并为进一步深入研究奠定基础，旨在确定这种新的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生物学背景下。与公共卫生相关：细胞对DNA损伤和其他类型的压力的反应是复杂的，但对细胞的健康非常重要。细胞对这些应激反应的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，我们打算描述一个新的基因BBEL1，它编码一种新的应激调节的E3泛素连接酶。BBEL1似乎是细胞应激反应通路的关键组成部分，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的关键的初步步骤，并为进一步深入研究奠定基础，旨在确定这种新的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生物学背景下。

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.