Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death

Abstract

The t(14; 18) chromosomal translocation of human follicular B-cell lymphoma juxtaposes the bcl-2 gene with the immunoglobulin heavy chain locus. The bcl-2 immunoglobulin fusion gene is markedly deregulated resulting in inappropriately elevated levels of bcl-2 RNA and protein. Transgenic mice bearing a bcl-2 immunoglobulin minigene demonstrate a polyclonal expansion of resting yet responsive IgM-IgD B cells which display prolonged cell survival but no increase in cell cycling. Moreover, deregulated bcl-2 extends the survival of certain haematopoietic cell lines following growth-factor deprivation. By using immunolocalization studies we now demonstrate that Bcl-2 is an integral inner mitochondrial membrane protein of relative molecular mass 25,000 (25k). Overexpression of Bcl-2 blocks the apoptotic death of a pro-B-lymphocyte cell line. Thus, Bcl-2 is unique among proto-oncogenes, being localized to mitochondria and interfering with programmed cell death independent of promoting cell division.

Evidence against a functional site for Bcl-2 downstream of caspase cascade in preventing apoptosis

“…However, since caspases possessing substrate speci®city similar to that of caspase-3 likely function most downstream in the caspase cascade, we conclude that there are no functional sites of Bcl-2 and Bcl-x L downstream of the caspase cascade. Although several groups have shown that Bcl-2 protein localizes in multiple membrane compartments (Hockenbery et al, 1990;Monaghan et al, 1992;Jacobson et al, 1993;Krajewski et al, 1993;Akao et al, 1994), it has not been convincingly determined in which subcellular compartment Bcl-2 acts to prevent cell death. Since active caspase-3 induces apoptotic changes of nuclei in vivo when microinjected into the cytoplasm (Yasuhara et al, 1997, and this study) and also in vitro when incubated with naked nuclei and cell lysates (Enari et al, 1996), caspase-3-mediated death signals or the caspase itself must be transferred from the cytoplasm to the nucleus to induce apoptotic nuclear changes.…”

“…Thus, Bcl-2 acts at least upstream of the activation of caspases. Bcl-2 localizes in multiple membrane compartments, including the nuclear envelope, endoplasmic reticulum and mitochondrial membranes (Hockenbery et al, 1990;Monaghan et al, 1992;Jacobson et al, 1993;Krajewski et al, 1993;Akao et al, 1994), raising the possibility that Bcl-2 also acts downstream of caspases. Indeed an anti-cell death role for Bcl-2 exerted downstream of active ICE family proteases has been suggested by the observations that (1) using in vitro apoptosis system, apoptotic DNA ladder formation is prevented by a Bcl-2-containing cell lysate, even after an e ector(s) downstream of caspases is activated, as judged by the failure of caspase inhibitors to prevent apoptotic changes in naked nuclei (Enari et al, 1995) and (2) apoptosis induced by transfection with caspase genes which encode precursor forms of proteases is prevented by overexpressed Bcl-2 (Miura et al, 1993;Wang et al, 1994).…”

Role of programmed cell death in the immunopathogenesis of sepsis

“…cytochrome c) into the cytosol. Cytosolic cytochrome c binds to Apaf-1, which oligomerizes to assemble the apoptosome that activates procaspase-9 and initiates a downstream caspase cascade resulting in cell death [10][11][12].…”

GRS, a novel member of the Bcl-2 gene family, is highly expressed in multiple cancer cell lines and in normal leukocytes

“…Bcl-2 functions in the process of programmed cell death and has been shown to block apoptosis (Hockenbery et al, 1990) in the absence of cell proliferation (Vaux et al, 1988). However, Bcl-2 de®cient mice exhibit normal prenatal developement although Bcl-2 expression is widespread during embryonic development (Veis et al, 1993).…”