Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression
Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression
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DOI：
10.1074/jbc.271.22.13055
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发表时间：
1996-05-31
影响因子：
4.8
通讯作者：
Henney, AM
中科院分区：
文献类型：
--
作者：
Ye, S;Eriksson, P;Henney, AM
在人基质分解素-1基因的启动子序列中存在常见的多态性，其中一个等位基因具有六个腺苷（6A）和其他五个腺苷（5A）的运行。我们先前报道，在冠状动脉粥样硬化患者的3年随访研究中，6A等位基因纯合子的那些患者显示疾病进展更快。我们已经研究了5A/6A启动子多态性是否在基质分解素-1基因表达的调节中起作用。在瞬时转染实验中，发现在多态性位点具有6A的基质分解素-1启动子构建体比含有5A的构建体表达更少的氯霉素乙酰转移酶报告基因。电泳迁移率变动分析和DNA酶I足迹法显示一个或多个核蛋白与5A/6A多态位点的DNA序列相互作用。与对应于5A等位基因的探针相比，用对应于6A等位基因的寡核苷酸探针更容易检测到核蛋白因子之一的结合。用随机DNA序列替换核心结合序列消除了核蛋白和探针之间的相互作用，并且还增加了瞬时转染细胞中的报告基因表达。因此，人基质分解素-1启动子的常见5A/6A多态性似乎在调节基质分解素-1基因表达中起重要作用，并且可能参与冠心病的进展。
There is a common polymorphism in the promoter sequence of the human stromelysin-1 gene, with one allele having a run of six adenosines (6A) and the other five adenosines (5A), We have previously reported, in a 3-year follow-up study of patients with coronary atherosclerosis, that those patients who are homozygous for the 6A allele show a more rapid progression of the disease, In this study, we have investigated whether the 5A/6A promoter polymorphism plays a role in the regu- lation of stromelysin-1 gene expression, In transient transfection experiments, a stromelysin-1 promoter construct with 6A at the polymorphic site was found to express less of the chloramphenicol acetyltransferase reporter gene than a construct containing 5A. Electrophoretic mobility shift assay and DNase I footprinting revealed the interaction of one or more nuclear protein(s) with the DNA sequence at the 5A/6A polymorphic site. The binding of one of the nucleoprotein factors was more readily detectable with an oligonucleotide probe corresponding to the 6A allele as compared with a probe corresponding to the 5A allele. Replacing the core binding sequence with a random DNA sequence abolished the interaction between the nuclear protein(s) and the probe and also increased reporter gene expression in transiently transfected cells. Thus, the common 5A/6A polymorphism of the human stromelysin-1 promoter appears to play an important role in regulating stromelysin-1 gene expression and may be involved in the progression of coronary heart disease.