Abstract
The disruption of mitochondrial function is a key component of apoptosis in most cell types. Localization of Bcl-2 to the outer mitochondrial and endoplasmic reticulum membranes is consistent with a role in the inhibition of many forms of apoptosis. In Rat-1 cells, a Bcl-2 mutant targeted exclusively to the endoplasmic reticulum (Bcl-cb5) was effective at inhibiting apoptosis induced by serum starvation/myc, or ceramide but not apoptosis induced by etoposide. The former conditions cause a decrease in mitochondrial transmembrane potential (Deltapsi(m)) as an early event that precedes the release of cytochrome c from mitochondria. By contrast, when cells are exposed to etoposide, a situation in which cytochrome c release and membrane localization of the pro-apoptotic protein Bax precede loss of Deltapsi(m), wild type Bcl-2 but not Bcl-cb5 prevents apoptosis. Therefore, Bcl-2 functions in spatially distinct pathways of apoptosis distinguished by the order of cytochrome c release and loss of Deltapsi(m).
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amino Acid Chloromethyl Ketones / pharmacology
-
Animals
-
Apoptosis / drug effects
-
Apoptosis / physiology*
-
Caspases / metabolism
-
Ceramides / pharmacology
-
Cysteine Proteinase Inhibitors / pharmacology
-
Cytochrome c Group / metabolism*
-
Endoplasmic Reticulum / metabolism*
-
Enzyme Activation
-
Etoposide / pharmacology
-
Fibroblasts / cytology
-
Fibroblasts / drug effects
-
Fibroblasts / physiology
-
Genes, myc / physiology
-
Intracellular Membranes / metabolism
-
Membrane Potentials / physiology
-
Mitochondria / drug effects
-
Mitochondria / metabolism
-
Mitochondria / physiology
-
Protein Conformation / drug effects
-
Proto-Oncogene Proteins / metabolism
-
Proto-Oncogene Proteins c-bcl-2 / genetics
-
Proto-Oncogene Proteins c-bcl-2 / metabolism
-
Proto-Oncogene Proteins c-bcl-2 / physiology*
-
Rats
-
Staurosporine / pharmacology
-
bcl-2-Associated X Protein
Substances
-
Amino Acid Chloromethyl Ketones
-
Bax protein, rat
-
Ceramides
-
Cysteine Proteinase Inhibitors
-
Cytochrome c Group
-
Proto-Oncogene Proteins
-
Proto-Oncogene Proteins c-bcl-2
-
bcl-2-Associated X Protein
-
benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
-
Etoposide
-
Caspases
-
Staurosporine