Nuclear factor-κB (NF-κB) inhibitory protein IκBβ determines apoptotic cell death following exposure to oxidative stress.
The transcription factor NF-κB regulates the cellular response to inflammatory and oxidant stress. Although many studies have evaluated NF-κB activity following exposure to oxidative stress, the role of the IκB family of inhibitory proteins in modulating this activity remains unclear. Specifically, the function of IκBβ in mediating the cellular response to oxidative stress has not been evaluated. We hypothesized that blocking oxidative stress-induced NF-κB signaling through IκBβ would prevent apoptotic cell death. Using IκBβ knock-in mice (AKBI), in which the IκBα gene is replaced with the IκBβ cDNA, we show that IκBβ overexpression prevented oxidative stress-induced apoptotic cell death. This was associated with retention of NF-κB subunits in the nucleus and maintenance of NF-κB activity. Furthermore, the up-regulation of pro-apoptotic genes in WT murine embryonic fibroblasts (MEFs) exposed to serum starvation was abrogated in AKBI MEFs. Inhibition of apoptosis was observed in WT MEFs overexpressing IκBβ with simultaneous IκBα knockdown, whereas IκBβ overexpression alone did not produce this effect. These findings represent a necessary but not sufficient role of IκBβ in preventing oxidant stress-induced cell death.
Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA. clyde.wright@ucdenver.edu
Clyde J
CJ
Wright
Fadeke
F
Agboke
Manasa
M
Muthu
Katherine A
KA
Michaelis
Miles A
MA
Mundy
Ping
P
La
Guang
G
Yang
Phyllis A
PA
Dennery
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002461:Cell Line, Transformed; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D020869:Gene Expression Profiling; D055879:Gene Knock-In Techniques; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D011247:Pregnancy; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D016895:Culture Media, Serum-Free; D020672:I-kappa B Proteins; C551354:IkappaBeta protein, mouse; D016328:NF-kappa B