BCL-2 family members and the mitochondria in apoptosis

  1. Atan Gross,
  2. James M. McDonnell, and
  3. Stanley J. Korsmeyer
  1. Departments of Pathology and Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 USA; The Rockefeller University, New York, New York 10021 USA

This extract was created in the absence of an abstract.

The BCL-2 family

A variety of physiological death signals, as well as pathological cellular insults, trigger the genetically programmed pathway of apoptosis (Vaux and Korsmeyer 1999). Apoptosis manifests in two major execution programs downstream of the death signal: the caspase pathway and organelle dysfunction, of which mitochondrial dysfunction is the best characterized (for reviews, see Green and Reed 1998; Thornberry and Lazebnik 1998). As the BCL-2 family members reside upstream of irreversible cellular damage and focus much of their efforts at the level of mitochondria, they play a pivotal role in deciding whether a cell will live or die (Fig. ).

Schematic model of mammalian cell death pathway. A major checkpoint in the common portion of this pathway is the ratio of pro-apoptotic (BAX) to anti-apoptotic (BCL-2) members. Downstream of this checkpoint are two major execution programs: the caspase pathway and mitochondria dysfunction. Mitochondrial dysfunction includes a change in the mitochondrial membrane potential (ΔΘm), production of reactive oxygen species (ROS), opening of the permeability transition pore (PTP), and the release of the intermembrane space protein, cytochrome c (Cyt c). Released cytochrome c activates Apaf-1, which in turn activates a downstream caspase program. Activated caspases can also effect the function of mitochondria. Caspases could be activated through Apaf-1/cytochrome c or directly by activation of cell surface death receptors. Caspases (e.g., caspase-3) are activated by two cleavage events that occur between the prodomain and the large subunit (p17) and between the large subunit and the small subunit (p12). The activated caspase, composed of two large and two small subunits, cleaves death substrates (e.g., PARP), which ultimately leads to cell death.

The founder of this family, the BCL-2 proto-oncogene, was discovered at the chromosomal breakpoint of t(14;18) bearing human B-cell lymphomas. The BCL-2 family of proteins has expanded significantly and includes both pro- as well …

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