The molecular mechanisms by which the Bcl-2 family regulates apoptosis

Bcl-2家族调控细胞凋亡的分子机制

• 批准号: 161201169
• 负责人: Dr. Dana Westphal
• 金额: --
• 依托单位: Molecular Genetics of Cancer Division
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/161201169?language=en
• 关键词: molecular; mechanisms; Bcl; family; regulates

Apoptosis plays vital roles in normal physiology, and its perturbed regulation underlies many disorders, including autoimmune diseases and cancer. Commitment to apoptosis is determined largely by interactions between members of the Bcl-2 protein family. As well as the pro-survival (Bcl-2-like) proteins, they include the BH3-only proteins, which transmit cytotoxic signals, and Bax and Bak, which permeabilize the mitochondria to initiate cell demolition. This proposal aims to clarify the critical interactions within the family that promote or inhibit cell death. The host laboratory has proposed that the pro-survival Bcl-2- like proteins bind to small subpopulations of the Bax and Bak proteins, residing at the mitochondria in a ‘primed stage’, and keep them in check. Upon a death signal, binding of the BH3-only proteins to the pro-survival proteins is posited to displace the primed Bax or Bak, allowing them to oligomerize and trigger apoptosis. I will test critical features of this novel model by attempting to identify the complexes of Bax with its pro-survival relatives, to prove that they are required for cell survival, to test whether BH3-only proteins can displace Bax, and to show that the freed Bax forms the oligomers that disrupt mitochondria. The findings should greatly clarify how apoptosis is normally controlled and thereby aid the development of the new anti-cancer drugs that target Bcl-2 family members.

细胞凋亡在正常生理学中发挥着至关重要的作用，其紊乱的调节是许多疾病的基础，包括自身免疫性疾病和癌症。细胞凋亡的发生很大程度上取决于 Bcl-2 蛋白家族成员之间的相互作用。除了促生存（Bcl-2 样）蛋白外，它们还包括仅 BH3 蛋白（可传递细胞毒性信号）以及 Bax 和 Bak（可透化线粒体以启动细胞破坏）。该提案旨在阐明家族内促进或抑制细胞死亡的关键相互作用。宿主实验室提出，促生存的 Bcl-2 样蛋白与 Bax 和 Bak 蛋白的小亚群结合，在“启动阶段”驻留在线粒体中，并对其进行控制。在死亡信号出现时，仅 BH3 蛋白与促存活蛋白的结合预计会取代已引发的 Bax 或 Bak，从而使它们寡聚并引发细胞凋亡。我将通过尝试识别 Bax 及其促生存亲属的复合物来测试这个新模型的关键特征，以证明它们是细胞生存所必需的，测试仅 BH3 的蛋白质是否可以取代 Bax，并证明释放的 Bax 形成破坏线粒体的寡聚物。这些发现应该极大地阐明细胞凋亡是如何正常控制的，从而有助于开发针对 Bcl-2 家族成员的新型抗癌药物。

项目成果

Apoptotic pore formation is associated with in-plane insertion of Bak or Bax central helices into the mitochondrial outer membrane

• DOI: 10.1073/pnas.1415142111
• 发表时间: 2014-09-30
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Westphal, Dana;Dewson, Grant;Kluck, Ruth M.
• 通讯作者: Kluck, Ruth M.

NMR studies of interactions between Bax and BH3 domain-containing peptides in the absence and presence of CHAPS.

在 CHAPS 不存在和存在的情况下 Bax 和含 BH3 结构域的肽之间相互作用的 NMR 研究

• DOI: 10.1016/j.abb.2014.01.003
• 发表时间: 2014
• 期刊: Archives of biochemistry and biophysics
• 影响因子: 3.9
• 作者: Westphal D;Babon J.J;Thompson G.V;Robin A.Y;Adams J.M;Colman P.M;Czabotar P.E.
• 通讯作者: Czabotar P.E.