Apoptotic Network Integrated at the Mitochondrion

线粒体整合的凋亡网络

• 批准号: 10005603
• 负责人: EMILY H CHENG
• 金额: $ 8.94万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005603
• 关键词: Adaptor Signaling Protein; Affect; Apoptosis; Apoptotic; BAX gene; BCL1 Oncogene; BCL2 gene; BCL2L11 gene; BIK gene; Biochemical Genetics; Biological Process; Caspase; Categories; Cell Death; Cessation of life; Cytosol; Cytotoxic Chemotherapy; Data; Development; Ensure; Family; Future; Genetic; Genetic study; Goals; Homeostasis; Homo; Human; Impairment; Knowledge; MCL1 gene; Maintenance; Malignant Neoplasms; Mediating; Membrane; Mitochondria; Modeling; Molecular; Morphology; Necrosis; Neurodegenerative Disorders; Organism; Outer Mitochondrial Membrane; PMAIP1 gene; Pathway interactions; Play; Protein Family; Refractory; Regulation; Role; Signal Transduction; Stimulus; Therapeutic; Therapeutic Intervention; Tumor Suppressor Proteins; Work; anti-cancer therapeutic; apoptotic protease-activating factor 1; base; c-myc Genes; cancer cell; cytochrome c; design; in vivo; loss of function; new therapeutic target; novel; parkin gene/protein; preservation; prevent; programs; protein complex; response; targeted cancer therapy; therapeutic target; tumor; tumor initiation; tumorigenesis

Project Summary Proper execution of cell death ensures normal biological processes, and its dysregulation causes human illness, ranging from cancer to neurodegenerative disorders. Apoptosis is a regulated form of cell death. Impairment of apoptosis is not only central to cancer development but also renders tumors refractory to cytotoxic therapy. Hence, further elucidation of the apoptotic signaling framework will not only help understand how cancer cells escape apoptotic checkpoints but also contribute to the development of rationally designed targeted cancer therapy. The BCL-2 family proteins govern cell death-versus-survival decisions at the mitochondria and can be divided into three subfamilies: (1) multidomain antiapoptotic BCL-2, BCL-XL and MCL-1; (2) multidomain proapoptotic BAX and BAK; and (3) proapoptotic BH3-only molecules (BH3s). BH3s relay upstream apoptotic signals to promote apoptosis by either activating BAX/BAK or inactivating BCL-2/BCL-XL/MCL-1. Genetic loss-of-function studies reveal an essential axis of upstream “activator” BH3s and downstream BAX/BAK in activating mitochondrion-dependent apoptosis. In response to apoptotic signals, the “activator” BH3s, including BID, BIM and PUMA, trigger the homo-oligomerization of BAX and BAK to permeabilize mitochondria, leading to the efflux of cytochrome c to the cytosol for caspase activation. We recently discovered a novel mechanism by which BH3s activate BAX/BAK- dependent mitochondrial permeabilization. We propose to elucidate this novel mechanism and reclassify BH3s based on their mechanisms in initiating cell death. Activation of BAX/BAK by BH3s not only triggers APAF-1-mediated caspase activation but also initiates caspase- independent cell death. Further characterization of this novel form of cell death holds promises for the future development of anti-cancer therapeutics that targets cancer cells with defective caspase activation. We are also pursing whether BAX and BAK reside in different protein complexes to differentially regulate caspase-dependent and -independent cell death programs. Overall, our goal is to build a comprehensive proapoptotic BCl-2 signaling network in activating mitochondrion-dependent cell death programs, which offers common ground for therapeutic interventions.

项目概要 细胞死亡的正确执行可确保正常的生物过程及其失调 细胞凋亡是导致人类疾病的一种原因，从癌症到神经退行性疾病。 细胞死亡的调节形式不仅是癌症发展的核心。 但也使肿瘤对细胞毒性治疗产生耐药性，因此需要进一步阐明。 凋亡信号传导框架不仅有助于理解癌细胞如何逃避凋亡 检查点还有助于合理设计的靶向癌症的发展 BCL-2 家族蛋白控制着细胞死亡与生存的决定。 线粒体，可分为三个亚家族：（1）多域抗凋亡 BCL-2， BCL-XL 和 MCL-1；(2) 多结构域促凋亡 BAX 和 BAK；和 (3) 仅促凋亡 BH3 分子（BH3）通过任一途径传递上游凋亡信号以促进细胞凋亡。 激活 BAX/BAK 或灭活 BCL-2/BCL-XL/MCL-1 遗传功能丧失研究。 揭示上游“激活剂”BH3 和下游 BAX/BAK 在激活过程中的重要轴 线粒体依赖性细胞凋亡。响应细胞凋亡信号，“激活剂”BH3， 包括 BID、BIM 和 PUMA，引发 BAX 和 BAK 的同源寡聚化， 使线粒体透化，导致细胞色素 c 流出到细胞质中用于 caspase 我们最近发现了 BH3 激活 BAX/BAK- 的新机制。 我们建议阐明这种新机制并 根据 BH3 启动 BAX/BAK 激活的机制对 BH3 进行重新分类。 BH3s 不仅触发 APAF-1 介导的 caspase 激活，而且还启动 caspase- 这种新型细胞死亡的进一步表征有望实现。 为未来开发针对有缺陷的癌细胞的抗癌疗法 我们也在探究BAX和BAK是否存在于不同的蛋白质中。 复合物差异调节半胱天冬酶依赖性和非依赖性细胞死亡程序。 总的来说，我们的目标是建立一个全面的促凋亡 BCl-2 信号网络，以激活 线粒体依赖性细胞死亡程序，为治疗提供了共同点 干预措施。

项目成果

BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program.

BID、BIM 和 PUMA 对于激活 BAX 和 BAK 依赖性细胞死亡程序至关重要。

• 发表时间: 2010-12-03
• 作者: Ren, Decheng;Tu, Ho;Kim, Hyungjin;Wang, Gary X;Bean, Gregory R;Takeuchi, Osamu;Jeffers, John R;Zambetti, Gerard P;Hsieh, James J;Cheng, Emily H
• 通讯作者: Cheng, Emily H

Targeting the differential addiction to anti-apoptotic BCL-2 family for cancer therapy.

针对癌症治疗中抗凋亡 BCL-2 家族的不同成瘾性。

• 发表时间: 2017
• 影响因子: 16.6
• 作者: Inoue;Jeng, Paul S;Kim, Kwanghee;Chen, Hui;Han, Song;Ganesan, Yogesh Tengarai;Ishizawa, Kota;Jebiwott, Sylvia;Dong, Yiyu;Pietanza, Maria C;Hellmann, Matthew D;Kris, Mark G;Hsieh, James J;Cheng, Emily H
• 通讯作者: Cheng, Emily H

Assembly of Bak homodimers into higher order homooligomers in the mitochondrial apoptotic pore.

在线粒体凋亡孔中将 Bak 同二聚体组装成更高阶的同寡聚体。

• 发表时间: 2016-08-04
• 影响因子: 4.6
• 作者: Mandal, Tirtha;Shin, Seungjin;Aluvila, Sreevidya;Chen, Hui;Grieve, Carter;Choe, Jun;Cheng, Emily H;Hustedt, Eric J;Oh, Kyoung Joon
• 通讯作者: Oh, Kyoung Joon

The p53-cathepsin axis cooperates with ROS to activate programmed necrotic death upon DNA damage.

p53-组织蛋白酶轴与 ROS 配合，在 DNA 损伤时激活程序性坏死性死亡。

• 发表时间: 2009-01-27
• 影响因子: 11.1
• 作者: Tu, Ho;Ren, Decheng;Wang, Gary X;Chen, David Y;Westergard, Todd D;Kim, Hyungjin;Sasagawa, Satoru;Hsieh, James J;Cheng, Emily H
• 通讯作者: Cheng, Emily H

ΔNp63 Inhibits Oxidative Stress-Induced Cell Death, Including Ferroptosis, and Cooperates with the BCL-2 Family to Promote Clonogenic Survival.

αNp63 抑制氧化应激诱导的细胞死亡，包括铁死亡，并与 BCL-2 家族合作促进克隆存活。

• DOI: 10.1016/j.celrep.2017.11.030
• 发表时间: 2017-12-05
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Wang GX;Tu HC;Dong Y;Skanderup AJ;Wang Y;Takeda S;Ganesan YT;Han S;Liu H;Hsieh JJ;Cheng EH
• 通讯作者: Cheng EH