Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription

被引:256
作者
In, KH
Asano, K
Beier, D
Grobholz, J
Finn, PW
Silverman, EK
Silverman, ES
Collins, T
Fischer, AR
Keith, TP
Serino, K
Kim, SW
DeSanctis, GT
Yandava, C
Pillari, A
Rubin, P
Kemp, J
Israel, E
Busse, W
Ledford, D
Murray, JJ
Segal, A
Tinkleman, D
Drazen, JM
机构
[1] BRIGHAM & WOMENS HOSP,DEPT MED,RESP DIS DIV,BOSTON,MA 02115
[2] BRIGHAM & WOMENS HOSP,DEPT PATHOL,BOSTON,MA 02115
[3] HARVARD UNIV,SCH MED,DEPT MED,BOSTON,MA 02115
[4] HARVARD UNIV,SCH MED,DEPT PATHOL,BOSTON,MA 02115
[5] GENOME THERAPEUT CORP,DEPT HUMAN & MOL GENET,WALTHAM,MA 02154
[6] ABBOTT LABS,ZILEUTON STUDY GRP,ABBOTT PK,IL 60064
关键词
leukotrienes; asthma;
D O I
10.1172/JCI119241
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Five lipoxygenase (5-LO) is the first committed enzyme in the metabolic pathway leading to the synthesis of the leukotrienes, We examined genomic DNA isolated from 25 normal subjects and 31 patients with asthma (6 of whom had aspirin-sensitive asthma) for mutations in the known transcription factor binding regions and the protein encoding region of the 5-LO gene, A family of mutations in the G + C-rich transcription factor binding region was identified consisting of the deletion of one, deletion of two, or addition of one zinc finger (Sp1/Egr-1) binding sites in the region 176 to 147 bp upstream from the ATG translation start site where there are normally 5 Sp1 binding moths in tandem, Reporter gene activity directed by any of the mutant forms of the transcription factor binding region was significantly (P < 0.05) less effective than the activity driven by the wild type transcription factor binding region. Electrophoretic mobility shift assays (EMSAs) demonstrated the capacity of wild type and mutant transcription factor binding regions to bind nuclear extracts from human umbilical vein endothelial cells (HUVECs). These data are consistent with a family of mutations in the 5-LO gene that can modify reporter gene transcription possibly through differences in Sp1 and Egr-1 transactivation.
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页码:1130 / 1137
页数:8
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