A20, a regulator of NFκB, maps to an atherosclerosis locus and differs between parental sensitive C57BL/6J and resistant FVB/N strains
Copyright policy )A20, a regulator of NFκB, maps to an atherosclerosis locus and differs between parental sensitive C57BL/6J and resistant FVB/N strains
An intercross between atherosclerosis susceptible (C57BL/6J ApoE0) and resistant (FVB/N ApoE0) mice revealed a susceptibility locus on chromosome 10 (11 cM, logarithm of odds 7.8). Surprisingly, the genotypic means for this locus revealed that heterozygosity or homozygosity for the C57BL/6J allele was associated with decreased atherosclerosis. A candidate gene in this region is A20, which is involved in the feedback suppression of NFκB activation induced by tumor necrosis factor α (TNFα). We sequenced the A20 gene coding region from the parental strains and found a single-nucleotide polymorphism resulting in a single amino acid exchange, Glu627Ala (C57BL/6J vs. FVB/N). This mutation introduces a putative casein kinase 2 phosphorylation site in C57BL/6J-A20 not present in FVB/N-A20. NFκB reporter gene assays showed that this amino acid change results in less effective termination of TNFα-stimulated NFκB activation by C57BL/6J-A20. In accordance, the TNFα-induced expression of NFκB target genes (A20, IκBα) in vascular smooth muscle cells was prolonged in cells isolated from C57BL/6J compared with FVB/N mice. In light of the genotypic means for atherosclerosis at the chromosome 10 locus in F 2 mice from this intercross, the observations now reported suggest that prolonged expression of genes induced by NFκB might be antirather than proatherogenic.
- Icahn School of Medicine at Mount Sinai United States
- Rockefeller University United States
Mice, Knockout, DNA, Complementary, Base Sequence, Arteriosclerosis, Intracellular Signaling Peptides and Proteins, NF-kappa B, Chromosome Mapping, Gene Expression, Nuclear Proteins, Polymorphism, Single Nucleotide, Muscle, Smooth, Vascular, Mice, Inbred C57BL, Cysteine Endopeptidases, Mice, Apolipoproteins E, Liver, NF-KappaB Inhibitor alpha, Animals, I-kappa B Proteins, Amino Acid Sequence
Mice, Knockout, DNA, Complementary, Base Sequence, Arteriosclerosis, Intracellular Signaling Peptides and Proteins, NF-kappa B, Chromosome Mapping, Gene Expression, Nuclear Proteins, Polymorphism, Single Nucleotide, Muscle, Smooth, Vascular, Mice, Inbred C57BL, Cysteine Endopeptidases, Mice, Apolipoproteins E, Liver, NF-KappaB Inhibitor alpha, Animals, I-kappa B Proteins, Amino Acid Sequence
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