John B. Little Center for Radiation Sciences, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
Lab for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
Nat Rev Mol Cell Biol. 2019 Mar;20(3):175-193. doi: 10.1038/s41580-018-0089-8.
The loss of vital cells within healthy tissues contributes to the development, progression and treatment outcomes of many human disorders, including neurological and infectious diseases as well as environmental and medical toxicities. Conversely, the abnormal survival and accumulation of damaged or superfluous cells drive prominent human pathologies such as cancers and autoimmune diseases. Apoptosis is an evolutionarily conserved cell death pathway that is responsible for the programmed culling of cells during normal eukaryotic development and maintenance of organismal homeostasis. This pathway is controlled by the BCL-2 family of proteins, which contains both pro-apoptotic and pro-survival members that balance the decision between cellular life and death. Recent insights into the dynamic interactions between BCL-2 family proteins and how they control apoptotic cell death in healthy and diseased cells have uncovered novel opportunities for therapeutic intervention. Importantly, the development of both positive and negative small-molecule modulators of apoptosis is now enabling researchers to translate the discoveries that have been made in the laboratory into clinical practice to positively impact human health.
健康组织中重要细胞的丧失是许多人类疾病（包括神经和传染病以及环境和医学毒性）的发生、发展和治疗结果的原因。相反，受损或多余细胞的异常存活和积累会导致突出的人类疾病，如癌症和自身免疫性疾病。细胞凋亡是一种进化上保守的细胞死亡途径，负责在正常真核生物发育和维持机体稳态过程中程序性清除细胞。该途径受 BCL-2 蛋白家族的控制，该家族包含促凋亡和抗凋亡成员，它们平衡细胞生死之间的决策。最近对 BCL-2 蛋白家族蛋白之间的动态相互作用以及它们如何控制健康和患病细胞中的细胞凋亡的深入了解，为治疗干预提供了新的机会。重要的是，凋亡的正、负小分子调节剂的开发现在使研究人员能够将实验室中的发现转化为临床实践，从而对人类健康产生积极影响。
