文章基本信息

标题：A20, a regulator of NFκB, maps to an atherosclerosis locus and differs between parental sensitive C57BL/6J and resistant FVB/N strains
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作者：Susanne Idel ; Hayes M. Dansky ; Jan L. Breslow 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：24
页码：14235-14240
DOI：10.1073/pnas.1835672100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 NF{kappa}B activation induced by tumor necrosis factor (TNF). 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. NF{kappa}B reporter gene assays showed that this amino acid change results in less effective termination of TNF-stimulated NF{kappa}B activation by C57BL/6J-A20. In accordance, the TNF-induced expression of NF{kappa}B target genes (A20, I{kappa}B) 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 NF{kappa}B might be antirather than proatherogenic.