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

细胞凋亡在正常生理中起着重要作用，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。凋亡的发生主要取决于Bcl-2蛋白家族成员之间的相互作用。除了促存活（Bcl-2样）蛋白，它们还包括传递细胞毒性信号的仅BH 3蛋白，以及使线粒体透化以启动细胞破坏的Bax和巴克。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Bcl-2样蛋白与Bax和巴克蛋白的小亚群结合，在“启动阶段”驻留在线粒体上，并使它们受到控制。在死亡信号时，仅BH 3蛋白与促存活蛋白的结合被假定为置换引发的Bax或巴克，使它们寡聚化并触发细胞凋亡。我将通过尝试识别Bax与其促生存亲属的复合物来测试这种新模型的关键特征，以证明它们是细胞存活所需的，以测试BH 3-only蛋白是否可以取代Bax，并表明释放的Bax形成破坏线粒体的寡聚体。这一发现将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家族成员的新抗癌药物。

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.