The Role of Non-C anonical Bax/Bak Direct Activators in Hematological Cancers

非典型 Bax/Bak 直接激活剂在血液癌症中的作用

• 批准号: 7697111
• 负责人: Melissa J Parsons
• 金额: $ 5.17万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-25 至 2011-08-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7697111
• 关键词: Apoptosis; Apoptotic; B-Cell Lymphomas; Bax protein; Biochemical; Caspase; Cell Death; Cells; Cytosol; Data; Disseminated Malignant Neoplasm; Genetic; Goals; Growth Factor; Hematologic Neoplasms; Hypoxia; Induction of Apoptosis; Knowledge; Lead; Liver Mitochondria; Malignant Neoplasms; Membrane; Mitochondria; Mus; Outer Mitochondrial Membrane; Pathway interactions; Phenotype; Property; Protein Family; Proteins; Research Personnel; Resistance; Role; Signal Transduction; TP53 gene; Tumor Cell Line; Tumor Suppression; cancer cell; carcinogenesis; cell killing; chemotherapeutic agent; major outer membrane protein; neoplastic cell; new therapeutic target; novel; programs; response; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): An important component of oncogenesis is the evasion of programmed cell death (also known as "apoptosis"), which is an essential mechanism of tumor suppression, as evasion of apoptosis is one of six acquired properties that result in a metastatic phenotype. Evasion of apoptosis offsets uncontrolled proliferation and can contribute to chemotherapeutic resistance, as many chemotherapeutic agents rely on induction of apoptosis in order to kill the cell. Apoptosis, and specifically the intrinsic mitochondrial pathway, relies on two Bcl-2 family proteins, Bax and Bak. Once activated, Bax and Bak oligomerize and produce mitochondrial outer membrane permeabilization, resulting in the release of intermembrane space proteins into the cytosol, thereby engaging downstream signaling cascades (such as caspase activation) that lead to the demise of the cell. To date, only three proteins are known to directly activate Bax and/or Bak: Bim, Bid and cytosolic p53. However, recent genetic and biochemical data suggest that mitochondrial apoptosis can proceed normally in the absence of these three proteins, indicating the existence of other "direct activators" of Bax and Bak. The goal of this proposal is to identify and characterize these non-canonical direct activators, and to explore their role in hematological cancers. Using genetic approaches, we will create cells that lack Bim, Bid and p53 expression in order to study the apoptotic response of cells lacking known direct activators of Bax and Bak. As a second approach to studying non-canonical direct activators, we will generate tumor cell lines from E?-myc mice lacking Bim and Bid expression, in order to examine whether such tumors contain functional non-canonical direct activators. Lastly, as a third approach, we will perform a large-scale screen for novel proteins that can act as direct activators. Loss of p53, Bim and Bid can contribute to carcinogenesis. It is therefore probable that loss of non-canonical direct activators can also contribute to cancer progression. Characterization of these proteins in hematological malignancies will enhance our knowledge of carcinogenesis, and provide researchers with important new therapeutic targets. Relevance: Cancer cells persist, in part, because they find ways to evade cell death, often through reducing expression of molecules that promote cell death, such as the proteins Bax and Bak and their activators, Bim, Bid and cytosolic p53. Recent genetic and biochemical evidence suggests proteins other than Bim, Bid and cytosolic p53 may exist, and if they do, they are likely dysregulated in cancer cells. Identifying and characterizing these non-canonical direct Bax/Bak activators and exploring their role in carcinogenesis will enhance our knowledge of carcinogenesis, and provide researchers with important new therapeutic targets.

描述（由申请人提供）：肿瘤发生的一个重要组成部分是逃避程序性细胞死亡（也称为“细胞凋亡”），这是肿瘤抑制的一个重要机制，因为逃避细胞凋亡是导致转移的六种后天特性之一表型。细胞凋亡的逃避抵消了不受控制的增殖，并可能导致化疗耐药性，因为许多化疗剂依赖于诱导细胞凋亡以杀死细胞。细胞凋亡，特别是内在的线粒体途径，依赖于两个Bcl-2家族蛋白，Bax和巴克。一旦被激活，Bax和巴克寡聚化并产生线粒体外膜透化，导致膜间空间蛋白释放到胞质溶胶中，从而参与导致细胞死亡的下游信号级联反应（如半胱天冬酶激活）。迄今为止，已知只有三种蛋白质直接激活Bax和/或巴克：Bim、Bid和胞质p53。然而，最近的遗传和生物化学数据表明，线粒体凋亡可以正常进行，在这三种蛋白质的情况下，表明存在其他“直接激活剂”的Bax和巴克。该提案的目标是识别和表征这些非典型的直接激活剂，并探索它们在血液癌症中的作用。使用遗传方法，我们将创建缺乏Bim，Bid和p53表达的细胞，以研究缺乏已知的Bax和巴克的直接激活剂的细胞的凋亡反应。作为研究非经典直接激活剂的第二种方法，我们将从E？缺乏Bim和Bid表达的myc小鼠，以检查此类肿瘤是否含有功能性非典型直接激活剂。最后，作为第三种方法，我们将进行大规模筛选，寻找可以作为直接激活剂的新型蛋白质。p53、Bim和Bid的缺失可促进癌发生。因此，非经典直接激活剂的丢失也可能导致癌症进展。这些蛋白质在血液恶性肿瘤中的特性将增强我们对肿瘤发生的认识，并为研究人员提供重要的新的治疗靶点。 相关性：癌细胞之所以能存活下来，部分原因是它们找到了逃避细胞死亡的方法，通常是通过减少促进细胞死亡的分子的表达，如蛋白Bax和巴克及其激活剂Bim、Bid和胞质p53。最近的遗传和生物化学证据表明，可能存在Bim、Bid和胞质p53以外的蛋白质，如果存在，它们可能在癌细胞中失调。识别和鉴定这些非经典的Bax/巴克直接激活剂并探讨它们在肿瘤发生中的作用将有助于我们对肿瘤发生的认识，并为研究人员提供重要的新的治疗靶点。