Endoplasmic reticulum localized Bcl-2 prevents apoptosis when redistribution of cytochrome c is a late event.
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).
Annis
M G
MG
Department of Biochemistry, McMaster University, Hamilton, L8N 3Z5, Canada.
Zamzami
N
N
Zhu
W
W
Penn
L Z
LZ
Kroemer
G
G
Leber
B
B
Andrews
D W
DW
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002518:Ceramides / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D016259:Genes, myc / Q000502:physiology; D007425:Intracellular Membranes / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011487:Protein Conformation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D019311:Staurosporine / Q000494:pharmacology; D051028:bcl-2-Associated X Protein
D000590:Amino Acid Chloromethyl Ketones; C494828:Bax protein, rat; D002518:Ceramides; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D005047:Etoposide; D020169:Caspases; D019311:Staurosporine