Bcl-2/Bax: A rheostat that regulates an anti-oxidant pathway and cell death

Stanley J. Korsmeyer, John R. Shutter, Deborah J. Veis, Diane E. Merry, Zoltan N. Oltvai

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766 Scopus citations

Abstract

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 oft(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 Box, a conserved homolog that helerodimerizes 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.

Original languageEnglish (US)
Pages (from-to)327-332
Number of pages6
JournalSeminars in Cancer Biology
Volume4
Issue number6
StatePublished - Dec 1 1993

Keywords

  • Apoptosis
  • Bcl-2
  • Cell death
  • Free radical
  • Oncogene

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