Apoptosis overrides survival signals through a caspase-mediated dominant-negative NF-kappa B loop.
The transcription factor NF-kappa B is an important regulator of gene expression during immune and inflammatory responses, and can also protect against apoptosis. Here we show that endothelial cells undergo apoptosis when deprived of growth factors. Surviving viable cells exhibit increased activity of NF-kappa B, whereas apoptotic cells show caspase-mediated cleavage of the NF-kappa B p65/ReIA subunit. This cleavage leads to loss of carboxy-terminal transactivation domains and a transcriptionally inactive p65 molecule. The truncated p65 acts as a dominant-negative inhibitor of NF-kappa B, promoting apoptosis, whereas an uncleavable, caspase-resistant p65 protects the cells from apoptosis. The generation of a dominant-negative fragment of p65 during apoptosis may be an efficient pro-apoptotic feedback mechanism between caspase activation and NF-kappa B inactivation.
Levkau
B
B
Department of Pathology, University of Washington, Seattle 98195-7470, USA.
Scatena
M
M
Giachelli
C M
CM
Ross
R
R
Raines
E W
EW
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation; D005246:Feedback; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D016328:NF-kappa B / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013379:Substrate Specificity; D051996:Transcription Factor RelA; D014158:Transcription, Genetic
D017931:DNA Primers; D016328:NF-kappa B; D051996:Transcription Factor RelA; D020169:Caspases