Bcl-2: an antidote to programmed cell death.
The maintenance of homoeostasis 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 programmed 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 proto-oncogenes in being localized to mitochondria and in blocking programmed cell death rather than affecting proliferation. In adults, bcl-2 is topographically restricted to progenitor cells and long-lived cells in tissues characterized by apoptotic cell death. Bcl-2 is confined to the zones of surviving B cells in germinal centres. Within thymus, bcl-2 is present in the surviving mature thymocytes of the medulla but absent from the majority of immature cortical thymocytes, most of which die by apoptosis. Transgenic mice that overexpress bcl-2 in the B cell lineage demonstrate extended cell survival and prolonged immune responses and indicate a role for bcl-2 in B cell memory. Transgenic models that overexpress bcl-2 in the thymus have expanded the involvement of bcl-2 to multiple apoptotic pathways and indicate its involvement in thymocyte maturation. Moreover, the development of tumours in transgenic mice that overexpress bcl-2 indicates the potential importance of oncogenes in interfering with programmed cell death. Alterations in genes that regulate cell death may prove to be key events in neoplasia, extending the life span of cells and thus increasing their opportunity to acquire additional genetic aberrations.
Korsmeyer
S J
SJ
Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, Missouri 63110.
D001402:B-Lymphocytes / Q000473:pathology; D016923:Cell Death; D002883:Chromosomes, Human, Pair 14; D002887:Chromosomes, Human, Pair 18; D019204:GTP-Binding Proteins / Q000235:genetics; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics* / Q000473:pathology*; D009857:Oncogenes / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2
D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011505:Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins