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

Key Points 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. 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. 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. 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. 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. 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). 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. 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. Apopt