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

Chenguang Fan; Jusan Yang; John F Engelhardt

doi:10.1242/jcs.00151

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

Journal article

Peer reviewed

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

Chenguang Fan, Jusan Yang and John F Engelhardt

Journal of cell science, Vol.115(Pt 24), pp.4843-4853

12/15/2002

DOI: 10.1242/jcs.00151

PMID: 12432072

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Abstract

The transcription factor NFkappaB is a critical immediate early response gene involved in modulating cellular responses and apoptosis following diverse environmental injuries. The activation of NFkappaB is widely accepted to play an anti-apoptotic role in cellular responses to injury. Hence, enhancing NFkappaB 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.IkappaBalphaAS) expressing antisense IkappaBalpha mRNA that is capable of augmenting NFkappaB 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 NFkappaB 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 IkappaBalpha. We hypothesized that activation of NFkappaB prior to injury using antisense IkappaBalpha mRNA would reduce apoptosis. As anticipated, recombinant adenoviral IkappaBalpha phosphorylation mutants (Ad.IkappaBalphaS32/36A or Ad.IkappaBalphaY42F) preferentially reduced NFkappaB activation and enhanced apoptosis following injuries associated with either serine or tyrosine phosphorylation of IkappaBalpha, respectively. These studies demonstrate for the first time that an IkappaBalphaY42F mutant can effectively modulate NFkappaB-mediated apoptosis in an injury-context-dependent manner. Interestingly, constitutive activation of NFkappaB following Ad.IkappaBalphaAS infection reduced apoptosis only following injuries associated with IkappaBalpha Y42, but not S32/36, phosphorylation. These findings demonstrate that the temporal regulation of NFkappaB and the apoptotic consequences of this activation are differentially influenced by the pathway mediating NFkappaB activation. They also provide new insight into the therapeutic potential and limitations of modulating NFkappaB for environmental injuries such as ischemia/reperfusion and pro-inflammatory diseases.

Phosphorylation

Signal Transduction

NF-KappaB Inhibitor alpha

Apoptosis - drug effects

Apoptosis - radiation effects

Humans

NF-kappa B - metabolism

I-kappa B Proteins - metabolism

RNA, Antisense - pharmacology

DNA Primers

Serine - metabolism

Cell Lineage

Tumor Necrosis Factor-alpha - pharmacology

Tyrosine - metabolism

Ultraviolet Rays

Base Sequence

Vanadates - pharmacology

HeLa Cells

Details

Title: Subtitle: Temporal pattern of NFκB activation influences apoptotic cell fate in a stimuli-dependent fashion
Creators: Chenguang Fan - Molecular Biology Graduate Program, University of Iowa College of Medicine, Iowa City, Iowa, 52242 USA
Jusan Yang
John F Engelhardt
Resource Type: Journal article
Publication Details: Journal of cell science, Vol.115(Pt 24), pp.4843-4853
Publisher: England
DOI: 10.1242/jcs.00151
PMID: 12432072
ISSN: 0021-9533
eISSN: 1477-9137
Grant note: DK51315 / NIDDK NIH HHS P50 HL60316 / NHLBI NIH HHS DK54759 / NIDDK NIH HHS
Language: English
Date published: 12/15/2002
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
Record Identifier: 9984025692502771

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