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A20, a regulator of NFkappaB, maps to an atherosclerosis locus and differs between parental sensitive C57BL/6J and resistant FVB/N strains.

ABSTRACT: 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 NFkappaB activation induced by tumor necrosis factor alpha (TNFalpha). 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. NFkappaB reporter gene assays showed that this amino acid change results in less effective termination of TNFalpha-stimulated NFkappaB activation by C57BL/6J-A20. In accordance, the TNFalpha-induced expression of NFkappaB target genes (A20, IkappaBalpha) 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 F2 mice from this intercross, the observations now reported suggest that prolonged expression of genes induced by NFkappaB might be antirather than proatherogenic.

SUBMITTER: Idel S

PROVIDER: S-EPMC283575 | biostudies-literature | 2003 Nov

REPOSITORIES: biostudies-literature

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A20, a regulator of NFkappaB, maps to an atherosclerosis locus and differs between parental sensitive C57BL/6J and resistant FVB/N strains.

Idel Susanne S Dansky Hayes M HM Breslow Jan L JL

Proceedings of the National Academy of Sciences of the United States of America 20031112 24

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 NFkappaB activation induced by tumor necrosis factor alpha (TNFal ...[more]

PMID: 14614151

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Project description:The role of the Ah locus in hexachlorobenzene (HCB)-induced porphyria and the possible involvement of P-450 cytochromes P(1)450 and P(3)450 in the pathogenesis of this disease were investigated in two congenic strains of C57BL/6J mice that differ only at this locus. Female B6-Ahb mice (Ah receptor: approximately 30-70 fmol/mg of cytosolic protein) and B6-Ahd mice (Ah receptor: undetectable) were pretreated with iron (500 mg/kg) and then fed a diet containing 0 or 200 p.p.m. of HCB for up to 17 weeks. Mice from the two strains consumed similar amounts of HCB. Urinary excretion of porphyrins was increased after 7 weeks of HCB treatment in B6-Ahb mice, and after 15 weeks was over 200 times greater than that of mice given iron only. In B6-Ahd mice, porphyrin excretion did not begin to increase until after 13 weeks, and after 15 weeks was only six times greater than that of controls. Similar differences were seen in the 15-week hepatic porphyrin concentrations (B6-Ahb: 1110 +/- 393; B6-Ahd: 17.6 +/- 14.5; controls: approximately 0.20 nmol/g). Uroporphyrinogen decarboxylase (EC 4.1.1.37) activity was diminished by 70 and 20% in B6-Ahb B6-Ahd mice respectively after 15 weeks of treatment with HCB. Cytochromes P(1)450 and P(3)450 were measured in hepatic microsomes (microsomal fractions) by radioimmunoassay and immunoblotting, using antisera raised against the orthologous rat isoenzymes P450c and P450d. HCB induced small amounts of a protein recognized by anti-P450c (P(1)450) in B6-Ahd mice, but not in B6-Ahd mice. Relatively large amounts of a protein recognized by anti-P450d (P(3)450) were induced in both strains, but to a somewhat greater extent in the B6-Ahb mice. The hepatic accumulation of HCB at 15 weeks was greater in B6-Ahb than in B6-Ahd mice, in association with elevated hepatic lipid levels in the former strain. The results of this experiment indicate that the Ah locus influences the susceptibility of C57BL/6J mice to HCB-induced porphyria and are consistent with the suggestion that the sustained induction of P(3)450 and/or P(1)450 may be a causative factor in the development of this disease.

Dataset Information

A20, a regulator of NFkappaB, maps to an atherosclerosis locus and differs between parental sensitive C57BL/6J and resistant FVB/N strains.

Publications

A20, a regulator of NFkappaB, maps to an atherosclerosis locus and differs between parental sensitive C57BL/6J and resistant FVB/N strains.

Similar Datasets

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