Correction

Ruben, Steven M.; Dillon, Patrick; Schreck, Ralf; Henkel, Thomas; Chen, C.-H.; Maher, Maureen; Baeuerle, Patrick A.; Rosen, Craig A.

doi:10.1126/science.254.5028.11.d

Cited by 14 publications

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

Induced stabilization of IκBα can facilitate its re‐synthesis and prevent sequential degradation

Place

Haspeslagh

Giardina

2003

Journal Cellular Physiology

View full text Add to dashboard Cite

The transcription factor NF-kappaB is responsible for regulating genes that can profoundly impact cell proliferation, apoptosis, inflammation, and immune responses. The NF-kappaB inhibitor IkappaBalpha is rapidly degraded and then re-synthesized after an NF-kappaB stimulus. We have found that the re-synthesis of IkappaBalpha in a human colon-derived cell line (HT-29) includes the post-translational stabilization of newly synthesized IkappaBalpha. The TNF-alpha-induced stabilization of newly synthesized IkappaBalpha involves the C-terminal PEST region of the protein: N-terminal deletion mutants (lacking the IkappaB kinase phosphorylation sites) were readily stabilized by TNF-alpha, whereas deletion of the C-terminus resulted in a constitutively stable protein. The role of the C-terminus in stabilization was further supported by the finding that fusion of the IkappaBalpha C-terminus to GFP generated a protein that could also be stabilized by TNF-alpha. The p38 mitogen-activated protein (MAP) kinase inhibitor SB203580 prevented stabilization of IkappaBalpha and delayed the re-emergence of IkappaBalpha following TNF-alpha-induced degradation. The IkappaBalpha stabilization pathway could prevent sequential rounds of IkappaBalpha degradation without preventing IkappaBalpha phosphorylation. Analysis of two other cell lines (SW480 and THP-1) revealed similarities and cell-specific differences in the regulation of IkappaBalpha stabilization. We propose that cytokine stabilization of newly synthesized IkappaBalpha in some cell types is a critical homeostatic mechanism that limits inflammatory gene expression.

show abstract

Induced stabilization of IκBα can facilitate its re‐synthesis and prevent sequential degradation

Place

Haspeslagh

Giardina

2003

Journal Cellular Physiology

View full text Add to dashboard Cite

show abstract

Nuclear factor‐κB decoy amelioration of spinal cord injury‐induced inflammation and behavior outcomes

Rafati

Geißler

Johnson

et al. 2007

J of Neuroscience Research

View full text Add to dashboard Cite

Spinal cord injury (SCI) results in a pathophysiology characterized by multiple locomotor and sensory deficits, resulting in altered nociception and hyperalgesia. SCI triggers an early and prolonged inflammatory response, with increased interleukin-1beta levels. Transient changes are observed in subunit populations of the transcription factor nuclear factor-kappaB (NF-kappaB). There were decreases in neuronal c-Rel levels and inverse increases in p65 and p50 levels. There were no changes in neuronal p52 or RelB subunits after SCI at any time point tested. Similarly, SCI had no effect on oligodendroglial levels of any NF-kappaB subunit. There were significant early increases in COX-2 and inducible nitric oxide synthase mRNA and protein levels after SCI. We used synthetic double-stranded "decoy" deoxyoligonucleotides containing selective NF-kappaB protein dimer binding consensus sequences. Decoys targeting the p65/p50 binding site on the COX-2 promoter decreased SCI-induced cell losses, NF-kappaB p65/p50 DNA-binding activity, and COX-2 and iNOS protein levels. NF-kappaB p65/p50 targeted decoys improved early locomotor recovery after moderate but not severe SCI, yet ameliorated SCI-induced hypersensitization after both moderate and severe SCI. To determine whether changes in GABA activity played a role in decreased hypersensitivity after SCI and p65/p50 targeted decoy, we counted gamma-aminobutyric acid (GABA)-containing neurons in laminae 1-3. There were significantly more GABAergic neurons in the p65/p50 targeted decoy-treated group at the level of injury.

show abstract