Modulation of NF-kappaB-dependent gene expression by H2O2: a major role for a simple chemical process in a complex biological response.
We recently observed that H2O2 regulates inflammation via upexpression of a few NF-kappaB-dependent genes, while leaving expression of most NF-kappaB-dependent genes unaltered. Here we test the hypothesis that this differential gene expression depends on the apparent affinity of kappaB sites in the gene-promoter regions toward NF-kappaB. Accordingly, cells were transfected with three reporter plasmids containing kappaB sequences with different affinities for NF-kappaB. It was observed that the lower the affinity, the higher the range of TNF-alpha concentrations where H2O2 upregulated gene expression. Mathematical models reproduced the key experimental observations indicating that H2O2 upregulation ceased when NF-kappaB fully occupied the kappaB sites. In vivo, it is predicted that genes with high-affinity sites remain insensitive to H2O2, whereas genes with lower-affinity sites are upregulated by H2O2. In conclusion, a simple chemical mechanism is at the root of a complex biologic process such as differential gene expression caused by H2O2.
Oliveira-Marques
Virgínia
V
Grupo de Bioquímica dos Oxidantes e Antioxidantes, Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisbon, Portugal. vmmarques@fc.ul.pt
Marinho
H Susana
HS
Cyrne
Luísa
L
Antunes
Fernando
F
D001483:Base Sequence; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D016328:NF-kappa B / Q000502:physiology*; D014158:Transcription, Genetic
D017931:DNA Primers; D016328:NF-kappa B; D006861:Hydrogen Peroxide