Regulation of Cell Death and Mitochondrial Physiology by Anti-Apoptotic MCL-1

抗凋亡 MCL-1 对细胞死亡和线粒体生理学的调节

基本信息

批准号：
7863093
负责人：
JOSEPH T. OPFERMAN
金额：
$ 42万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7863093
关键词：
Ablation Address Affect Apoptosis Apoptotic Autoimmunity Binding Biochemical Biology Blood Cells Bone Marrow Cancerous Cell Death Cell Survival Cells Cessation of life Defect Development Equilibrium Exhibits Family member Generations Genetic Goals Hematopoiesis Hematopoietic Immunodeficiency and Cancer Individual Inner mitochondrial membrane Laboratories Lead Light Location Lymphocyte Macromolecular Complexes Maintenance Mediating Membrane Membrane Potentials Mind Mitochondria Nature Normal Cell Outer Mitochondrial Membrane Physiology Play Positioning Attribute Production Reactive Oxygen Species Regulation Resistance Role Seminal Series Staging Stimulus United States National Institutes of Health cancer cell experience human disease innovation mitochondrial membrane mutant neutrophil novel prevent progenitor public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Anti-apoptotic BCL-2 family members regulate hematopoiesis and when dysregulated contribute to cancer, immunodeficiency, and autoimmunity. MCL-1 is absolutely required for cell survival at multiple stages of hematopoietic development. In contrast, genetic ablation of Bcl-2 or Bcl-X has revealed specific roles in promoting hematopoietic survival. Why MCL-1 plays such a critical role in maintaining survival and why the concomitant endogenous expression of other anti-apoptotic regulators cannot compensate for MCL-1 loss has remained unresolved. Therefore, the long term goal of my laboratory is to understand how MCL-1 functions and is regulated during hematopoietic development and survival. To understand the requirement for MCL-1 in development, we have recently identified that it localizes to both the outer mitochondrial membrane, where it MCL-1 binds and sequesters pro-apoptotic molecules, and to the mitochondrial inner membrane as an N- terminally truncated form. The contribution of both of these localizations to MCL-1's function is unclear. The objective of this proposal is to dissect the functional roles of the two mitochondrial forms of MCL-1 and to assess the individual roles of these localizations in promoting cellular survival. Our central hypothesis is that the outer membrane form of MCL-1 acts like "classical" BCL-2 family members to antagonize pro-apoptotics, while the inner membrane form of MCL-1 regulates cell survival by modulating mitochondrial function. The studies we propose will reveal a previously unrecognized role for MCL-1 and shed light onto a new mechanism by which an anti-apoptotic BCL-2 family member promotes mitochondrial function. Aim 1: Define the role(s) for the different mitochondrial forms of MCL-1 in regulating hematopoiesis. MCL-1 exhibits a profound requirement during many stages of hematopoiesis, but it is unclear why. Aim 2: Define the role(s) of inner mitochondrial MCL-1 in regulating apoptosis. Our preliminary studies indicate that only the outer mitochondrial form of MCL-1 is capable of binding and sequestering pro-apoptotic molecules. However, it is unclear whether the inner mitochondrial form of MCL-1 may alter response to death stimuli. Therefore, we will investigate how the different forms of MCL-1 contribute to its "classical" anti-apoptotic nature. Aim 3: Identify how MCL-1 regulates mitochondrial physiology. Our preliminary studies indicate that Mcl-1-deficiency results in abnormalities in mitochondrial physiology even when cells are not undergoing apoptosis. My laboratory has made many of the seminal findings defining the role of MCL-1 in promoting survival during hematopoiesis. Furthermore, we are uniquely positioned to successfully perform these studies as we have identified the novel localization, generated MCL-1 mutants that can dissect the different forms of MCL-1, and have extensive experience in MCL-1 biology. At the end of this study, we will have illuminated a previously unrecognized role for MCL-1 in promoting mitochondrial function. PUBLIC HEALTH RELEVANCE: Defects in the balance of cell survival and death can lead to a variety of human diseases including autoimmunity, immunodeficiency, and cancer. MCL-1 is a critical regulator of blood cell survival whose expression is tightly controlled in normal cells, but in cancerous cells such control is lost leading to inappropriate survival. This proposal is relevant to the goals of the National Institutes of Health because it investigates a novel role for MCL-1 in normal blood cells and will assess how MCL-1 can render cancer cells resistant to death.

描述（由申请人提供）：抗凋亡 BCL-2 家族成员调节造血作用，当失调时会导致癌症、免疫缺陷和自身免疫。 MCL-1 对于造血发育多个阶段的细胞存活是绝对必需的。相比之下，Bcl-2 或 Bcl-X 的基因消除揭示了促进造血存活的特定作用。为什么 MCL-1 在维持生存中发挥如此关键的作用，以及为什么其他抗凋亡调节因子的伴随内源表达无法补偿 MCL-1 的损失，仍然没有得到解决。因此，我实验室的长期目标是了解 MCL-1 在造血发育和存活过程中如何发挥作用并受到调节。为了了解发育过程中对 MCL-1 的需求，我们最近发现它定位于线粒体外膜（MCL-1 在此结合并隔离促凋亡分子）和线粒体内膜（作为 N 端截短的分子）。形式。这两种定位对 MCL-1 功能的贡献尚不清楚。该提案的目的是剖析 MCL-1 两种线粒体形式的功能作用，并评估这些定位在促进细胞存活中的各自作用。我们的中心假设是，MCL-1 的外膜形式像“经典”BCL-2 家族成员一样发挥拮抗促凋亡作用，而 MCL-1 的内膜形式通过调节线粒体功能来调节细胞存活。我们提出的研究将揭示 MCL-1 以前未被认识的作用，并揭示抗凋亡 BCL-2 家族成员促进线粒体功能的新机制。目标 1：定义不同线粒体形式的 MCL-1 在调节造血功能中的作用。 MCL-1 在造血的许多阶段都表现出深刻的需求，但原因尚不清楚。目标 2：确定线粒体内部 MCL-1 在调节细胞凋亡中的作用。我们的初步研究表明，只有 MCL-1 的外线粒体形式能够结合和隔离促凋亡分子。然而，目前尚不清楚 MCL-1 的内部线粒体形式是否可能改变对死亡刺激的反应。因此，我们将研究不同形式的 MCL-1 如何有助于其“经典”抗凋亡特性。目标 3：确定 MCL-1 如何调节线粒体生理学。我们的初步研究表明，即使细胞没有发生凋亡，Mcl-1 缺陷也会导致线粒体生理学异常。我的实验室做出了许多开创性的发现，定义了 MCL-1 在促进造血过程中存活的作用。此外，我们处于成功开展这些研究的独特地位，因为我们已经确定了新的定位，生成了可以剖析不同形式的 MCL-1 的 MCL-1 突变体，并且在 MCL-1 生物学方面拥有丰富的经验。在这项研究结束时，我们将阐明 MCL-1 在促进线粒体功能方面的先前未被认识的作用。公共卫生相关性：细胞生存和死亡平衡的缺陷可能导致多种人类疾病，包括自身免疫、免疫缺陷和癌症。 MCL-1 是血细胞存活的关键调节因子，其表达在正常细胞中受到严格控制，但在癌细胞中这种控制丧失，导致不适当的存活。该提案与美国国立卫生研究院的目标相关，因为它研究了 MCL-1 在正常血细胞中的新作用，并将评估 MCL-1 如何使癌细胞抵抗死亡。