AI Article Synopsis
- The NF-kappaB pathway stimulation leads to the presence of p65-p50 and p50-p50 dimers in the cell nucleus, with a specific focus on the TNF promoter region.
- A natural genetic variation at nucleotide -863 inhibits p50-p50 binding to the NF-kappaB site without affecting p65-p50 binding, impacting gene expression regulation.
- Findings suggest that p50-p50 can hinder the activity of p65-p50, highlighting how small genetic changes can influence inflammatory gene regulation in humans.
Article Abstract
Stimulation of the NF-kappaB pathway often causes p65-p50 and p50-p50 dimers to be simultaneously present in the cell nucleus. A natural polymorphism at nucleotide -863 in the human TNF promoter (encoding tumor necrosis factor [TNF]) region provides an opportunity to dissect the functional interaction of p65-p50 and p50-p50 at a single NF-kappaB binding site. We found that this site normally binds both p65-p50 and p50-p50, but a single base change specifically inhibits p50-p50 binding. Reporter gene analysis in COS-7 cells expressing both p65-p50 and p50-p50 shows that the ability to bind p50-p50 reduces the enhancer effect of this NF-kappaB site. Using an adenoviral reporter assay, we found that the variant which binds p50-p50 results in a reduction of lipopolysaccharide-inducible gene expression in primary human monocytes. This finding adds to a growing body of experimental evidence that p50-p50 can inhibit the transactivating effects of p65-p50 and illustrates the potential for genetic modulation of inflammatory gene regulation in humans by subtle nucleotide changes that alter the relative binding affinities of different forms of the NF-kappaB complex.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC102169 | PMC |
| http://dx.doi.org/10.1128/MCB.20.24.9113-9119.2000 | DOI Listing |
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