The first mammalian regulator emerged when bcl-2, the gene activated by chromosome translocation in human follicular lymphoma, was unexpectedly found to permit the survival of cytokine-dependent hematopoietic cells, in a quiescent state, in the absence of cytokine. At least 15 Bcl-2 family members have been identified in mammalian cells and several others in viruses. All members possess at least one of four conserved motifs known as Bcl-2 homology domains (BH1 to BH4). Most pro-survival members, which can inhibit apoptosis in the face of a wide variety of cytotoxic insults, contain at least BH1 and BH2, and those most similar to Bcl-2 have all four BH domains. The two pro-apoptotic subfamilies differ markedly in their relatedness to Bcl-2. Bax, Bak, and Bok (also called Mtd), which contain BH1, BH2, and BH3, resemble Bcl-2 fairly closely.
Bcl-2 directly or indirectly prevents the release from mitochondria of cytochrome c, which [along with adenosine triphosphate (ATP)] may facilitate a change in Apaf-1 structure to allow procaspase-9 recruitment and processing. Precluding cytochrome c release is unlikely to be the sole function of Bcl-2, because Bcl-2 can protect cells after much has been released, and microinjected cytochrome c does not kill all cell types. The Bcl-2 family is regulated by cytokines and other death-survival signals at different levels. Several pro-survival genes are induced transcriptionally by certain cytokines, and bax is induced in some cells as part of the p53-mediated damage response. Bcl-2 protects against diverse cytotoxic insults—for example, g- and ultraviolet-irradiation, cytokine withdrawal, dexamethasone, staurosporine, and cytotoxic drugs.With the discovery of the anti-apoptotic function of the bcl-2 oncogene, the concept emerged that a raised threshold for apoptosis represents a central step in tumorigenesis.