Function and regulation of the BCL-2 family

BCL-2家族的功能和调节

• 批准号: 8080602
• 负责人: Jerry Edward Chipuk
• 金额: $ 35.04万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8080602
• 关键词: Apoptosis; Apoptotic; BAX gene; BCL-2 Protein; BCL1 Oncogene; Biochemical; Biological; Biological Markers; Biological Models; Biology; Cancer Biology; Cancer Etiology; Caspase; Cells; Clinic; Collaborations; Complement; Curiosities; Cytoplasm; Cytosol; Data; Development; Excision; Exhibits; Family; Foundations; Future; Genetic; Goals; In Vitro; Knowledge; Length; Lipids; Literature; Lymphomagenesis; Maintenance; Malignant Neoplasms; Mediating; Mitochondria; Oncogenes; Outcome; Outer Mitochondrial Membrane; Pathway interactions; Play; Process; Protein Family; Proteins; Proteolipids; RNA Interference; Radiation; Recombinant Proteins; Regulation; Research; Role; Signal Pathway; Signal Transduction; Specificity; Sphingolipids; Sphingomyelins; Sphingosine; Work; cancer cell; cancer therapy; cell injury; cell suicide; chemotherapy; design; enzyme pathway; experience; in vivo; inhibitor/antagonist; interest; killings; malignant state; membrane model; metaplastic cell transformation; neoplastic cell; novel; prevent; prognostic; programs; reconstitution; research study; response; small molecule; success; tool; tumor; tumor initiation; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The impact of the apoptotic pathways on cancer biology is broad because the BCL-2 family of proteins regulates nearly all steps of tumor progression, exhibits prognostic value, and can be predictive of treatment success. In the clinic, tumor cells die in response to chemotherapeutics and radiation treatment by inducing apoptosis, which has generated substantial enthusiasm for dissecting how this pathway proceeds and may be pharmacologically modulated. Apoptosis proceeds when the BCL-2 family of proteins promotes mitochondrial outer membrane permeabilization (MOMP), which triggers the release of pro-apoptotic molecules from mitochondria into the cytoplasm. Two BCL-2 family proteins, BAK and BAX, directly engage MOMP by creating proteolipid pores in the outer mitochondrial membrane. BAK/BAX-dependent MOMP is required for apoptosis, and is initiated by a BCL-2 family subset, the BH3-only proteins, e.g., BID. Our studies recently discovered that in order for BAK/BAX and BID to induce MOMP, mitochondria must functionally intersect with the sphingolipid pathway. The novel hypothesis is that mitochondrial sphingolipids confer function to the BCL-2 family, which may explain how BAK/BAX and BID specifically target mitochondria. Curiosity in the BCL-2 family-mitochondrial interactions mentioned above led to the identification that the sphingolipid pathway plays a crucial role in BCL-2 family function. We recently identified that two products within the sphingolipid pathway, sphingosine-1-PO4 and hexadecenal, directly regulate BAK and BAX activation, respectively. The goals of the current application are focused on understanding the mechanistic contribution of sphingosine-1-PO4 and hexadecenal on BCL-2 family function, MOMP and apoptosis. This project emerged following years of effort to identify cellular components necessary for MOMP, and we propose three specific aims: (1) to explore the biochemical requirements for the sphingolipid pathway on BID-induced BAK/BAX activation, (2) to elucidate the functional cooperation between BAK/BAX and the sphingolipid pathway in the contexts of cellular fate and tumorigenesis, and (3) to probe the structural relationships between BAX and hexadecenal necessary to promote MOMP and apoptosis. The scientific outcome of this proposal will uncover novel mechanisms of BCL-2 family regulation and commitment to apoptosis. These data will elucidate the functional and structural interaction(s) between BAK/BAX and the sphingolipids, and serve as the foundation for the development of BAK/BAX pharmacologic regulators in the future. PUBLIC HEALTH RELEVANCE: Cancer occurs when cells acquire changes that convert them from a normal to malignant state. Apoptosis is a program of cellular suicide that eliminates damaged cells to prevent cancer; yet the body also turns on this program following chemotherapy and radiation treatments in order to kill cancer cells. Therefore, it is important to investigate the pathways that control apoptosis to understand how cancer occurs and should be treated.

描述（由申请人提供）：细胞凋亡途径对癌症生物学的影响是广泛的，因为 BCL-2 蛋白家族调节肿瘤进展的几乎所有步骤，表现出预后价值，并且可以预测治疗成功。在临床上，肿瘤细胞通过诱导细胞凋亡响应化疗和放射治疗而死亡，这引起了人们对剖析该途径如何进行以及如何进行药理学调节的极大热情。当 BCL-2 蛋白家族促进线粒体外膜透化 (MOMP) 时，细胞凋亡就会发生，从而触发促凋亡分子从线粒体释放到细胞质中。两种 BCL-2 家族蛋白 BAK 和 BAX 通过在线粒体外膜上形成蛋白脂质孔来直接与 MOMP 结合。 BAK/BAX 依赖性 MOMP 是细胞凋亡所必需的，并且由 BCL-2 家族子集（仅 BH3 蛋白，例如 BID）启动。我们最近的研究发现，为了使 BAK/BAX 和 BID 诱导 MOMP，线粒体必须在功能上与鞘脂途径相交。新的假设是线粒体鞘脂赋予 BCL-2 家族功能，这可能解释 BAK/BAX 和 BID 如何专门针对线粒体。 对上述 BCL-2 家族与线粒体相互作用的好奇使人们认识到鞘脂通路在 BCL-2 家族功能中起着至关重要的作用。我们最近发现鞘脂途径中的两种产物，鞘氨醇-1-PO4 和十六碳烯醛，分别直接调节 BAK 和 BAX 激活。当前应用的目标集中于了解 sphingosine-1-PO4 和十六碳烯醛对 BCL-2 家族功能、MOMP 和细胞凋亡的机制贡献。经过多年努力确定 MOMP 所需的细胞成分，该项目应运而生，我们提出了三个具体目标：(1) 探索 BID 诱导的 BAK/BAX 激活中鞘脂通路的生化要求，(2) 阐明功能BAK/BAX 与鞘脂通路在细胞命运和肿瘤发生中的合作；(3) 探讨 BAX 与促进 MOMP 和细胞凋亡所必需的十六碳烯醛之间的结构关系。该提案的科学成果将揭示 BCL-2 家族调控和细胞凋亡的新机制。这些数据将阐明BAK/BAX与鞘脂之间的功能和结构相互作用，并为未来开发BAK/BAX药理调节剂奠定基础。 公共卫生相关性：当细胞发生从正常状态转变为恶性状态的变化时，就会发生癌症。细胞凋亡是一种细胞自杀程序，可消除受损细胞以预防癌症；然而，在化疗和放射治疗后，身体也会启动这个程序来杀死癌细胞。因此，研究控制细胞凋亡的途径对于了解癌症如何发生以及如何治疗非常重要。