The induction of apoptosis by diverse death stimuli occurs through the transcriptional or posttranscriptional regulation of BH3-only proteins.

Levels of Noxa and Puma are transcriptionally upregulated by p53 in response to DNA damage. Cytokines and growth factors act as survival factors by inhibiting the proapoptotic activities of Bad and Bim through changes in the state of protein phosphorylation. Loss of cell adherence to extracellular matrix can lead to a form of apoptosis termed “anoikis,” and this is regulated by BH3 proteins that associate with actin filaments (Bmf) or microtubules (Bim). The caspase 8-mediated cleavage of Bid to form tBid acts as a link between the extrinsic and intrinsic pathways of apoptosis. BH3-only proteins translocate to the mitochondria, where they can bind to antiapoptotic (Bcl-2, Bcl-XL, Mcl-1) or proapoptotic (Bax, Bak) Bcl-2 family members to regulate mitochondrial outer membrane permeability (MOMP) and the release of cytochrome c, apoptosis-inducing factor (AIF), and SMAC/Diablo (see Figure 6). Bax is cytosolic until death signals induce a conformational change followed by its insertion into the outer mitochondrial membrane with formation of oligomers. Recent studies demonstrate that the level of Ca⁺² stores in the endoplasmic reticulum (ER) and subsequent uptake of Ca⁺² by the mitochondria play an important role in determining the threshold for apoptosis. This cyclical ER-mitochondrial flux of Ca⁺² is regulated in part by Bax, Bak, Bcl-2 and other family members that are localized to these organelles. Abbreviations: IMS, inter-membrane space; SMAC, second mitochondrial activator of caspases; PKA, protein kinase A