Function and regulation of the BCL-2 family

BCL-2家族的功能和调节

• 批准号: 8268982
• 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/8268982
• 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.

描述（由申请人提供）：凋亡通路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，具有预后价值，并且可以预测治疗成功。在临床中，肿瘤细胞在化疗和放疗后通过诱导细胞凋亡而死亡，这引起了人们对解剖这一途径如何进行和可能被药理学调节的极大热情。当BCL-2蛋白家族促进线粒体外膜渗透（MOMP）时，细胞凋亡就发生了，MOMP触发促凋亡分子从线粒体释放到细胞质中。两个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直接参与MOMP。BAK/ bax依赖性MOMP是细胞凋亡所必需的，由BCL-2家族亚群BH3-only蛋白（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通路相交。新的假设是线粒体鞘脂赋予BCL-2家族功能，这可以解释BAK/BAX和BID如何特异性靶向线粒体。对BCL-2家族的好奇使得我们发现鞘脂通路在BCL-2家族功能中起着至关重要的作用。我们最近发现鞘脂通路中的两种产物鞘脂素-1- po4和十六烯醛分别直接调节BAK和BAX的激活。目前的研究目的是了解鞘氨醇-1- po4和十六烯醛对BCL-2家族功能、MOMP和细胞凋亡的作用机制。本项目是在多年研究MOMP所需细胞成分的基础上产生的，我们提出了三个具体目标：(1)探索bid诱导的BAK/BAX激活对鞘脂通路的生化要求；(2)阐明BAK/BAX与鞘脂通路在细胞命运和肿瘤发生过程中的功能合作；(3)探索BAX与促进MOMP和细胞凋亡所需的十六烯醛之间的结构关系。这一建议的科学成果将揭示BCL-2家族调控和承诺凋亡的新机制。这些数据将阐明BAK/BAX与鞘脂之间的功能和结构相互作用，并为今后BAK/BAX药理调节剂的开发奠定基础。