Function and regulation of the BCL-2 family

BCL-2家族的功能和调节

基本信息

批准号：
8633008
负责人：
Jerry Edward Chipuk
金额：
$ 33.99万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
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/8633008
关键词：
Apoptosis Apoptotic BAX gene BCL-2 Protein BCL2 gene Biochemical Biological 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 Prognostic Marker Protein Family Proteins Proteolipids RNA Interference Radiation Recombinant Proteins Regulation Research Role Signal Pathway Signal Transduction Specificity Sphingolipids Sphingomyelins Sphingosine Work biophysical properties 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 protein protein interaction reconstitution research study response small molecule success tool tumor tumor initiation tumor progression tumorigenesis

项目摘要

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）：凋亡途径对癌症生物学的影响很广，因为Bcl-2蛋白质家族几乎调节肿瘤进展的所有步骤，表现出预后价值，并且可以预测治疗成功。在诊所中，肿瘤细胞因诱导凋亡而响应化学治疗和放射治疗而死亡，这对剖析该途径的进行方式产生了极大的热情，并且可以在药理学上进行调节。当蛋白的Bcl-2家族促进线粒体外膜通透性（MOMP）时，凋亡会进行，这会触发从线粒体释放到细胞质中的促凋亡分子。两种Bcl-2家族蛋白Bak和Bax通过在外部线粒体膜上产生蛋白脂毛来直接吸引MOMP。凋亡需要BAK/BAX依赖性MOMP，并由Bcl-2家族子集，仅BH3蛋白（例如BID）发起。我们的研究最近发现，为了使BAK/BAX并出价诱导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将功能赋予Bcl-2家族，这可以解释BAK/BAX和BID如何专门针对线粒体。上面提到的BCL-2家族体相互作用中的好奇心导致识别鞘脂途径在Bcl-2家族功能中起着至关重要的作用。我们最近确定，鞘脂途径中的两种产物分别直接调节BAK和BAX激活。当前应用的目标集中在理解鞘氨酸-1-PO4和六核对Bcl-2家族功能，MOMP和凋亡的机理贡献。 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促进MOMP和凋亡所需的BAX和十六进制之间的结构关系。该提案的科学结果将发现BCL-2家族调节的新机制和对凋亡的承诺。这些数据将阐明Bak/Bax和鞘脂之间的功能和结构相互作用，并将其作为未来BAK/BAX药理调节剂开发的基础。