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doi: 10.1242/10.1242/jcs.00151

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Journal of Cell Science 115, 4843-4853 (2002)
doi: 10.1242/jcs.00151

Research Article

Temporal pattern of NF{kappa}B activation influences apoptotic cell fate in a stimuli-dependent fashion

Chenguang Fan1,2,3, Jusan Yang2,3 and John F. Engelhardt1,2,3,*

1 Molecular Biology Graduate Program, University of Iowa College of Medicine, Iowa City, Iowa, 52242 USA
2 The Center for Gene Therapy, University of Iowa College of Medicine, Iowa City, Iowa, 52242 USA
3 Department of Anatomy and Cell Biology, University of Iowa College of Medicine, Iowa City, Iowa, 52242 USA

* Author for correspondence (e-mail: john-engelhardt{at}uiowa.edu)

Accepted 4 September 2002

The transcription factor NF{kappa}B is a critical immediate early response gene involved in modulating cellular responses and apoptosis following diverse environmental injuries. The activation of NF{kappa}B is widely accepted to play an anti-apoptotic role in cellular responses to injury. Hence, enhancing NF{kappa}B activation in the setting of injury has been proposed as one potential therapeutic approach to environmental injuries. To this end, we constructed a recombinant adenoviral vector (Ad.I{kappa}B{alpha}AS) expressing antisense I{kappa}B{alpha} mRNA that is capable of augmenting NF{kappa}B activation prior to and following four types of cellular injury [TNF-{alpha}, UV, hypoxia/reoxygenation (H/R) or pervanadate treatment]. Biochemical and functional analyses of NF{kappa}B activation pathways for these injuries demonstrated two categories involving either serine (S32/36) phosphorylation (TNF-{alpha}, UV) or tyrosine (Y42) phosphorylation (H/R or PV) of I{kappa}B{alpha}. We hypothesized that activation of NF{kappa}B prior to injury using antisense I{kappa}B{alpha} mRNA would reduce apoptosis. As anticipated, recombinant adenoviral I{kappa}B{alpha} phosphorylation mutants (Ad.I{kappa}B{alpha}S32/36A or Ad.I{kappa}B{alpha}Y42F) preferentially reduced NF{kappa}B activation and enhanced apoptosis following injuries associated with either serine or tyrosine phosphorylation of I{kappa}B{alpha}, respectively. These studies demonstrate for the first time that an I{kappa}B{alpha}Y42F mutant can effectively modulate NF{kappa}B-mediated apoptosis in an injury-context-dependent manner. Interestingly, constitutive activation of NF{kappa}B following Ad.I{kappa}B{alpha}AS infection reduced apoptosis only following injuries associated with I{kappa}B{alpha} Y42, but not S32/36, phosphorylation. These findings demonstrate that the temporal regulation of NF{kappa}B and the apoptotic consequences of this activation are differentially influenced by the pathway mediating NF{kappa}B activation. They also provide new insight into the therapeutic potential and limitations of modulating NF{kappa}B for environmental injuries such as ischemia/reperfusion and pro-inflammatory diseases.

Key words: Antisense inhibition, NF{kappa}B activation, Signal transduction, Apoptosis






© The Company of Biologists Ltd 2002