REACTIVE OXYGEN SPECIES AND THE REGULATION OF CELL-DEATH BY THE BCL-2GENE FAMILY

The maintenance of homeostasis in normal tissues reflects a balance be tween cell proliferation and cell death. Bcl-2 inaugurated a new categ ory of oncogenes, regulators of cell death. The Bcl-2 gene was identif ied at the chromosomal breakpoint of t(14;18) bearing B cell lymphomas . Bcl-2 proved unique by blocking programmed cell death rather than pr omoting proliferation, In adults, Bcl-2 is topographically restricted to progenitor cells and longlived cells but is much more widespread in the developing embryo, Transgenic mice that overexpress Bcl-2 demonst rate extended cell survival, and progress to high grade lymphomas. Bcl -2 has been localized to mitochondria, endoplasmic reticulum and nucle ar membranes, also the sites of reactive oxygen species generation. Bc l-2 does not appear to influence the generation of oxygen free radical s but does prevent oxidative damage to cellular constituents including lipid membranes. Bcl-2 deficient mice complete embryonic development but undergo fulminant lymphoid apoptosis of thymus and spleen. Moreove r, they demonstrate two unexpected pathologies resulting from cell dea th, polycystic kidney disease and hair hypopigmentation. The latter is a potential oxidant injury from the melanin biosynthetic pathway. A f amily of Bcl-2 related genes is emerging that includes Bar, a conserve d homolog that heterodimerizes in vivo with Bcl-2 and promotes cell de ath. The ratio of family members, such as Bcl-2/Bax, determines the su rvival or death of cells following an apoptotic stimulus.