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doi: 10.1242/10.1242/jcs.00151

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Temporal pattern of NFB activation influences apoptotic cell fate in a stimuli-dependent fashion

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 NFB is a critical immediate early response gene involved in modulating cellular responses and apoptosis following diverse environmental injuries. The activation of NFB is widely accepted to play an anti-apoptotic role in cellular responses to injury. Hence, enhancing NFB 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.IBAS) expressing antisense IB mRNA that is capable of augmenting NFB activation prior to and following four types of cellular injury [TNF-, UV, hypoxia/reoxygenation (H/R) or pervanadate treatment]. Biochemical and functional analyses of NFB activation pathways for these injuries demonstrated two categories involving either serine (S32/36) phosphorylation (TNF-, UV) or tyrosine (Y42) phosphorylation (H/R or PV) of IB. We hypothesized that activation of NFB prior to injury using antisense IB mRNA would reduce apoptosis. As anticipated, recombinant adenoviral IB phosphorylation mutants (Ad.IBS32/36A or Ad.IBY42F) preferentially reduced NFB activation and enhanced apoptosis following injuries associated with either serine or tyrosine phosphorylation of IB, respectively. These studies demonstrate for the first time that an IBY42F mutant can effectively modulate NFB-mediated apoptosis in an injury-context-dependent manner. Interestingly, constitutive activation of NFB following Ad.IBAS infection reduced apoptosis only following injuries associated with IB Y42, but not S32/36, phosphorylation. These findings demonstrate that the temporal regulation of NFB and the apoptotic consequences of this activation are differentially influenced by the pathway mediating NFB activation. They also provide new insight into the therapeutic potential and limitations of modulating NFB for environmental injuries such as ischemia/reperfusion and pro-inflammatory diseases.

Key words: Antisense inhibition, NFB activation, Signal transduction, Apoptosis

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