FUNCTIONAL HOMOLOGY BETWEEN ACTIVE BAX AND BACTERIOPHAGE HOLIN

活性 BAX 和噬菌体 Holin 之间的功能同源性

• 批准号: 8360445
• 负责人: Xu Luo
• 金额: $ 7.35万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360445
• 关键词: Apoptosis; BAX gene; Bacteria; Bacteriophages; Biological Models; Cell Death; Cells; Cytolysis; Development; Elements; Funding; Genetic; Grant; Homeostasis; Homo; Lesion; Link; Malignant Neoplasms; Mediating; Membrane; Mitochondria; National Center for Research Resources; Nebraska; Organism; Outer Mitochondrial Membrane; Pathway interactions; Principal Investigator; Protein Family; Research; Research Infrastructure; Resources; Signal Transduction; Source; Testing; Therapeutic; Tissues; United States National Institutes of Health; Work; cancer cell; cost; insight; mutant; novel; tumor progression

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Apoptosis is a cell death program critical for orchestrating development and maintaining tissue homeostasis of multi-cellular organisms. Aberrant blockade of apoptosis is associated the development and progression of cancer. On the other hand, most cancer therapeutics function by inducing apoptosis in cancer cells. The mitochondria-dependent pathway is primarily responsible for apoptosis, and is largely regulated by the Bcl-2 family proteins at the step of mitochondrial outer membrane permeabilization (MOMP). The mechanism of Bax/Bak-dependent MOMP during apoptosis remains poorly understood. Our preliminary studies found that active mutants of Bax or Bak are potent inducers of bacterial cell lysis and cell death. More importantly, they function in a fashion similar to that of bacteriophage holin. Our hypothesis is that active Bax functions as a holin to cause bacterial membrane lesions. In Aim 1, we propose to examine the structural elements of Bax that are mediating the bacterial lysis activity. In Aim 2, we propose to examine the requirement of homo-oligomerization for the bacterial lysis activity of active Bax. In Aim 3, we propose to examine the bacterial inner membrane localization of active Bax, and identify the bacterial membrane targeting sequence of Bax. In Aim 4, we propose to test the functional and genetic replacement of holin in lamda bacteriophage. These studies are expected to mechanistically linked MOMP to holin-mediated hole formation in the bacterial membrane. If successful, this work will provide novel insights into the mechanism of MOMP, and establish bacteria as a powerful model system for the study of apoptosis.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其他NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 细胞凋亡是一种细胞死亡程序，对于协调多细胞生物体的发育和维持组织稳态至关重要。 细胞凋亡的异常阻断与癌症的发生和发展相关。 另一方面，大多数癌症治疗剂通过诱导癌细胞凋亡来起作用。细胞凋亡主要是由Bcl-2家族蛋白介导的线粒体外膜透化（MOMP）途径引起的。Bax/Bak-dependent MOMP在细胞凋亡过程中的作用机制仍知之甚少。 我们的初步研究发现，Bax或巴克的活性突变体是细菌细胞裂解和细胞死亡的有效诱导剂。 更重要的是，它们的功能类似于噬菌体holin。 我们的假设是，活性Bax作为一个洞蛋白的功能，导致细菌膜病变。 在目的1中，我们建议检查介导细菌裂解活性的Bax的结构元件。 在目标2中，我们提出研究同源寡聚化对活性Bax的细菌裂解活性的要求。 目的3：研究Bax的细菌内膜定位，并鉴定Bax的细菌膜靶向序列。 在目的4中，我们提出测试λ噬菌体中holin的功能和遗传替代。 这些研究预计将MOMP与细菌膜中holin介导的孔形成机制联系起来。 如果成功，这项工作将提供新的见解MOMP的机制，并建立细菌作为一个强大的模型系统的研究细胞凋亡。