Function and regulation of the BCL-2 family

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于化疗和放射治疗而死亡，这产生了大量的热情来剖析该途径如何进行并且可能是可调节的。当BCL-2蛋白家族促进线粒体外膜透化（MOMP）时，细胞凋亡进行，这触发促细胞凋亡分子从线粒体释放到细胞质中。两种BCL-2家族蛋白质巴克和BAX通过在线粒体外膜中产生蛋白脂质孔而直接接合MOMP。巴克/BAX依赖性MOMP是细胞凋亡所必需的，并且由BCL-2家族亚群，仅BH 3蛋白，例如，BID.我们最近的研究发现，为了使巴克/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，这可以解释巴克/BAX和BID如何特异性靶向线粒体。 上述BCL-2家族-线粒体相互作用中的突变导致了鞘脂途径在BCL-2家族功能中起关键作用的鉴定。我们最近发现，鞘脂途径内的两种产品，鞘氨醇-1-PO 4和十六烯醛，直接调节巴克和BAX激活，分别。本申请的目标集中于理解鞘氨醇-1-PO 4和十六烯醛对BCL-2家族功能、MOMP和凋亡的机制贡献。该项目是在多年努力确定MOMP所需的细胞成分后出现的，我们提出了三个具体目标：（1）探索鞘脂途径对BID诱导的巴克/BAX活化的生化要求，（2）阐明巴克/BAX和鞘脂途径在细胞命运和肿瘤发生背景下的功能合作，（3）探讨BAX和十六烯醛之间的结构关系，它们是促进MOMP和细胞凋亡所必需的。该提案的科学成果将揭示BCL-2家族调控和细胞凋亡承诺的新机制。这些数据将阐明巴克/BAX与鞘脂之间的功能和结构相互作用，并为将来开发巴克/BAX药理学调节剂奠定基础。 公共卫生相关性：当细胞获得将其从正常状态转化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，消除受损细胞以预防癌症;然而，在化疗和放射治疗后，身体也会启动这一程序，以杀死癌细胞。因此，重要的是要研究控制细胞凋亡的途径，以了解癌症是如何发生的，应该如何治疗。

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.