Binding of upstream stimulatory factor 1 to the E-Box regulates the 4G/5G polymorphism-dependent plasminogen activator inhibitor 1 expression in mast cells

被引：21
作者：
Ma, Zhongcai [1 ]
Jhun, BongSook [1 ]
Jung, Sandy Y. [1 ]
Oh, Chad K. [1 ]
机构：
[1] Harbor UCLA Med Ctr, Div Allergy & Immunol, Sch Med, Dept Pediat, Torrance, CA 90502 USA
来源：
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY | 2008年 / 121卷 / 04期
关键词：
plasminogen activator inhibitor 1; 4G/5G polymorphism; transcription; human mast cells; upstream stimulatory factor 1; E-box;
D O I：
10.1016/j.jaci.2007.11.015
中图分类号：
R392 [医学免疫学];
学科分类号：
100102 ;
摘要：
Background: Plasminogen activator inhibitor (PAI)-1 is a key regulator of the fibrinolytic system. PAI-1 levels are markedly elevated in the asthmatic airways. The 4G/5G polymorphism of the PAI-1 gene is associated with allergic asthma. Objective: To characterize the mechanisms of the 4G/5G-dependent PAI-1 expression in mast cells (MCs), a major source of PAI-1 and key effector cells in asthma. Methods: Transcription of PAI-1 was assessed by transiently transfecting human MC line (HMC-1) cells with the luciferasetagged PAI-1 promoters containing the 4G or 5G allele (4G-PAI-1 or 5G-PAI-1 promoter). Upstream stimulatory factor (USF)-1 and the E-box interactions were studied by electrophoretic mobility shift assays and supershift assays. Expression of USF-1 was determined by Western blot analysis. Results: The 4G-PAI-1 promoter has higher promoter activity than the 5G-PAI-1 promoter in stimulated HMC-1 cells, and the E-box adjacent to the 4G/5G site (E-4G/5G) regulates the genotype-specific PAI-1 transcription. USF-1 binds to the E-4G with greater affinity than to the E-5G. USF-1 level is increased in HMC-1 cells after stimulation, and elevated USF-1 enhances PAI-1 transcription. Overexpression of wild-type USF-1 or dominant-negative USF remedies the 4G/5G-dependent PAI-1 transcription. Conclusion: Binding of USF-1 to the E-4G/5G regulates the 4G/5G polymorphism-dependent PAI-1 expression in MCs.
引用
收藏
页码：1006 / 1012
页数：7
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