Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death.
The maintenance of homeostasis in normal tissues reflects a balance between cell proliferation and cell death. The importance of both positive and negative regulators of cell growth has been well documented in neoplasia. Bcl-2 argues for the existence of 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 has proved to be unique among protooncogenes in 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 in the B cell lineage 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 and display relatively normal haematopoietic differentiation but undergo fulminant lymphoid apoptosis of thymus and spleen. Moreover, they demonstrate two potentially oxidation related pathologies: polycystic kidney disease and hair hypopigmentation. A family of bcl-2 related genes is emerging that includes Bax, a conserved homolog that heterodimerizes in vivo with bcl-2. A pre-set ratio of Bcl-2/Bax appears to determine the survival or death of cells following an apoptotic stimulus.
Korsmeyer
S J
SJ
Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, MO 63110.
Shutter
J R
JR
Veis
D J
DJ
Merry
D E
DE
Oltvai
Z N
ZN
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002883:Chromosomes, Human, Pair 14 / Q000648:ultrastructure; D002887:Chromosomes, Human, Pair 18 / Q000648:ultrastructure; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D011519:Proto-Oncogenes; D017382:Reactive Oxygen Species; D014178:Translocation, Genetic; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C494827:Bax protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein