Reactive oxygen species and the regulation of cell death by the Bcl-2 gene family.
The maintenance of homeostasis in normal tissues reflects a balance between cell proliferation and cell death. Bcl-2 inaugurated a new category of oncogenes, regulators of cell death. The Bcl-2 gene was identified at the chromosomal breakpoint of t(14;18) bearing B cell lymphomas. Bcl-2 proved unique by blocking programmed cell death rather than promoting 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 demonstrate extended cell survival, and progress to high grade lymphomas. Bcl-2 has been localized to mitochondria, endoplasmic reticulum and nuclear membranes, also the sites of reactive oxygen species generation. Bcl-2 does not appear to influence the generation of oxygen free radicals 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. Moreover, they demonstrate two unexpected pathologies resulting from cell death, polycystic kidney disease and hair hypopigmentation. The latter is a potential oxidant injury from the melanin biosynthetic pathway. A family of Bcl-2 related genes is emerging that includes Bax, a conserved homolog that heterodimerizes in vivo with Bcl-2 and promotes cell death. The ratio of family members, such as Bcl-2/Bax, determines the survival or death of cells following an apoptotic stimulus.
Korsmeyer
S J
SJ
Department of Medicine, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110, USA.
Yin
X M
XM
Oltvai
Z N
ZN
Veis-Novack
D J
DJ
Linette
G P
GP
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D016923:Cell Death / Q000502:physiology*; D002883:Chromosomes, Human, Pair 14; D002887:Chromosomes, Human, Pair 18; D006706:Homeostasis; D006801:Humans; D008223:Lymphoma / Q000235:genetics; D008969:Molecular Sequence Data; D005810:Multigene Family; D009857:Oncogenes; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D011519:Proto-Oncogenes; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014178:Translocation, Genetic
D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species