Lamb Heather M, Hardwick Marie
Bloomberg School of Public Health, Johns Hopkins University, Department of Molec Microb and Immunol, 615 N Wolfe St., Baltimore, Maryland 21205, USA.
Adv Exp Med Biol. 2010;687:115-29. doi: 10.1007/978-1-4419-6706-0_7.
BCL-2 family proteins form heterodimers or homo-oligomers to inhibit or induce apoptotic cell death, respectively. They often relocalize from the cytoplasm to mitochondria to carry out these functions. The traditional model is that in healthy cells, anti-death family members hold pro-death BCL-2 family members in check. Upon receiving a death stimulus, another set of proteins (BH3-only proteins) inactivate the protective BCL-2 proteins, forcing them to release their pro-death partners that are subsequently triggered to oligomerize and porate the mitochondrial outer membrane leading to cell death. In support of this traditional view, there is a preponderance of supporting evidence derived from the study of events that occur following treatment of cells with a death stimulus. Knockout and mutant mice also exhibit many developmental and treatment-induced phenotypes consistent with this model of antagonism between BCL-2 family proteins. Emphasis is logically placed on those phenotypes that support the model. However, this working model of BCL-2 family interactions has become so engrained that alternative, potentially valid interpretations are sometimes dismissed. Therefore, it is useful to consider the evidence that seems contrary to accepted models. In particular, the analysis of BCL-2 family functions in the nervous system has revealed unexpected outcomes that can serve to further stimulate critical probing of the yet unknown biochemical functions of BCL-2 proteins.
BCL-2家族蛋白分别形成异源二聚体或同源寡聚体来抑制或诱导凋亡性细胞死亡。它们常常从细胞质重新定位到线粒体以执行这些功能。传统模型认为，在健康细胞中，抗死亡家族成员抑制促死亡的BCL-2家族成员。在受到死亡刺激后，另一组蛋白（仅含BH3结构域的蛋白）使保护性BCL-2蛋白失活，迫使它们释放其促死亡伙伴，这些伙伴随后被触发寡聚化并使线粒体外膜形成孔道，导致细胞死亡。支持这一传统观点的是，在用死亡刺激处理细胞后发生的事件的研究中有大量支持证据。基因敲除和突变小鼠也表现出许多与BCL-2家族蛋白之间这种拮抗模型一致的发育和治疗诱导的表型。逻辑上重点关注那些支持该模型的表型。然而，这种BCL-2家族相互作用的工作模型已经根深蒂固，以至于有时会摒弃其他可能有效的解释。因此，考虑那些似乎与公认模型相悖的证据是很有用的。特别是，对神经系统中BCL-2家族功能的分析揭示了意想不到的结果，这些结果可进一步激发对BCL-2蛋白未知生化功能的深入探究。
