文章：

Bcl2家族：细胞生死开关的调节器

The Bcl2 family: regulators of the cellular life-or-death switch

原文发布日期：2002-09-01

DOI: 10.1038/nrc883

类型: Review Article

开放获取: 否

要点：

1. Apoptosis, the cell-death programme that is mediated by proteases called caspases, is essential for tissue homeostasis, and its perturbed regulation underlies many diseases, including cancer. Commitment to apoptosis in response to diverse physiological cues and cytotoxic agents is governed by proteins of the Bcl2 family.
2. Bcl2 and several pro-survival relatives associate with the mitochondrial outer membrane and the endoplasmic reticulum/nuclear membrane and maintain their integrity. Initiation of apoptosis requires not only pro-apoptotic family members such as Bax and Bak that closely resemble Bcl2, but also distant cousins that are related only by the small BH3 protein-interaction domain.
3. The BH3-only proteins are sentinels that detect developmental death cues or intracellular damage. In healthy cells, they are restrained in diverse ways, including sequestration on the cytoskeleton. When unleashed by death signals, they switch off survival function by inserting their BH3 domain into a groove on their pro-survival relatives.
4. Either Bax or Bak is required for apoptosis, but how they are activated or countermanded by Bcl2 remains uncertain. During apoptosis, Bax and Bak oligomerize in the mitochondrial outer membrane and probably breach its integrity, freeing pro-apoptotic proteins such as cytochrome c, which allows activation of caspase-9.
5. The pro-survival Bcl2-like proteins can prevent cytochrome c release, and hence caspase-9 activation. They probably also regulate the activation of several other caspases, independently of mitochondrial damage.
6. Impaired apoptosis is a central step towards neoplasia. Pro-survival Bcl2-like proteins can promote tumorigenesis, and certain pro-apoptotic relatives act as tumour suppressors. Moreover, the expression of family members is affected by other tumorigenic alterations (for example, p53 mutation).
7. Conventional cytotoxic therapy indirectly induces apoptosis, but more effective outcomes should be achieved by direct activation of the apoptotic machinery. Promising approaches include impairing expression of pro-survival Bcl2-like proteins or identifying drugs that mimic the action of BH3-only proteins.

要点翻译：

1. 细胞凋亡是由被称为半胱天冬酶的蛋白酶介导的细胞死亡程序，对维持组织稳态至关重要，其调控紊乱是包括癌症在内的多种疾病的根本原因。Bcl2家族蛋白质负责响应多种生理信号和细胞毒性物质，决定细胞是否启动凋亡程序。
2. Bcl2及其多种促存活同源蛋白定位于线粒体外膜和内质网/核膜，维持这些膜结构的完整性。凋亡启动不仅需要与Bcl2高度相似的促凋亡家族成员（如Bax和Bak），还需要仅通过小型BH3蛋白相互作用结构域相关联的远亲蛋白。
3. 仅含BH3结构域的蛋白质是监测发育性死亡信号或细胞内损伤的哨兵。在健康细胞中，它们通过多种方式被抑制，包括被隔离在细胞骨架上。当死亡信号释放这些蛋白时，它们通过将BH3结构域插入促存活同源蛋白的沟槽来关闭生存功能。
4. 凋亡过程需要Bax或Bak参与，但其激活机制及Bcl2的抑制作用仍不明确。凋亡过程中，Bax和Bak在线粒体外膜发生寡聚化，可能破坏膜完整性，释放细胞色素c等促凋亡蛋白，从而激活半胱天冬酶-9。
5. 促存活的Bcl2样蛋白能阻止细胞色素c释放，进而抑制半胱天冬酶-9的激活。它们可能还独立于线粒体损伤途径，调控其他多种半胱天冬酶的激活。
6. 凋亡功能受损是肿瘤发生的关键环节。促存活的Bcl2样蛋白会促进肿瘤形成，而某些促凋亡家族成员则发挥抑癌作用。此外，该家族成员的表达还受其他致瘤性改变（如p53突变）的影响。
7. 传统细胞毒性疗法通过间接方式诱导凋亡，但直接激活凋亡机制应能获得更佳疗效。前景良好的策略包括：抑制促存活Bcl2样蛋白的表达，或研发模拟仅含BH3结构域蛋白作用的药物。

英文摘要：

Tissue homeostasis is regulated by apoptosis, the cell-suicide programme that is executed by proteases called caspases. The Bcl2 family of intracellular proteins is the central regulator of caspase activation, and its opposing factions of anti- and pro-apoptotic members arbitrate the life-or-death decision. Apoptosis is often impaired in cancer and can limit conventional therapy. A better understanding of how the Bcl2 family controls caspase activation should result in new, more effective therapeutic approaches.

摘要翻译： 

组织稳态由细胞自杀程序——凋亡所调控，该程序由称为半胱天冬酶的蛋白酶执行。细胞内蛋白Bcl2家族是半胱天冬酶激活的核心调控者，其抗凋亡与促凋亡两派成员共同裁决细胞的生死。凋亡在癌症中常被抑制，并可限制常规治疗。更深入理解Bcl2家族如何调控半胱天冬酶激活，将有助于开发出更新、更有效的治疗策略。

原文链接：

The Bcl2 family: regulators of the cellular life-or-death switch