Apoptosis promotes a caspase-induced amino-terminal truncation of IkappaBalpha that functions as a stable inhibitor of NF-kappaB.
Caspases are cell death cysteine proteases that are activated upon the induction of the apoptotic program and cleave target proteins in a sequence-specific manner to promote cell death. Recently, Barkett et al. (Barkett, M., Xue, D., Horvitz, H. R., and Gilmore, T. D. (1997) J. Biol. Chem. 272, 29419-29422) have shown that IkappaBalpha, the inhibitory subunit of the transcription factor NF-kappaB, can be cleaved by caspase-3 in vitro at a site that potentially produces a dominant inhibitory form of IkappaBalpha. The involvement of NF-kappaB in the inhibition of cell death led us to ask whether apoptotic stimuli would induce the caspase-mediated cleavage of IkappaBalpha in vivo. In this study, we show that apoptosis leads to the caspase-mediated amino-terminal truncation of IkappaBalpha (DeltaN-IkappaBalpha). Our data show that DeltaN-IkappaBalpha can bind NF-kappaB, suppress NF-kappaB activation, and sensitize cells to death. Since activated NF-kappaB plays a role in the inhibition of cell death, these data suggest that caspase-mediated cleavage of IkappaBalpha may be a mechanism to suppress NF-kappaB and its associated antiapoptotic activity.
Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina 27599-7295, USA.
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JY
Reuther
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Baldwin
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D017931:DNA Primers; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases