Mechanisms regulating expression of the tumor necrosis factor-related light gene -: Role of calcium-signaling pathway in the transcriptional control

被引:20
作者
Castellano, R
Van Lint, C
Péri, V
Veithen, E
Morel, Y
Costello, R
Olive, D
Collette, Y
机构
[1] INSERM, U119, Inst Cancerol & Immunol Marseille, F-13009 Marseille, France
[2] Free Univ Brussels, Inst Biol & Med Mol, Chim Biol Lab, B-6041 Gosselies, Belgium
[3] Inst J Paoli I Calmettes, Lab Immunol Tumeurs, F-13009 Marseille, France
关键词
D O I
10.1074/jbc.M207689200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
LIGHT (TNFSF14) is a newly identified tumor necrosis factor superfamily member involved in the regulation of immune responses by control of activation, maturation, and survival of immune effector cells. Despite the immunological relevance of the LIGHT protein, little knowledge is available as to how light gene expression is regulated. In T-lymphocytes, most LIGHT surface expression and transcript accumulation occurs after T cell activation. In this study, we have shown that these events are blocked at the transcriptional level by cyclosporin A, an immuno-suppressive drug. Besides, we identified a role for Ca2+-signaling pathways and NFAT transcription factors in T cell activation-induced LIGHT expression. To further investigate this process, we have identified, cloned, and characterized a 2.1-kilobase 5'-flanking DNA genomic fragment from the human light gene. We have shown the transcriptional activity of the herein-identified minimal 5' regulatory region of human light gene parallels the endogenous expression of light in T cells. Moreover, we demonstrated that induced LIGHT promoter activity can be equally blocked by cyclosporin A treatment or dominant negative NFAT overexpression and further identified by site-directed mutagenesis and electrophoretic mobility supershift analysis of a NFAT transcription factor binding site within the human light minimal promoter. Finally, Sp1 and Ets1 binding sites were identified and shown to regulate light basal promoter activity. Thus, the present study establishes a molecular basis to further understand the mechanisms governing human light gene expression and, consequently, could potentially lead to novel therapeutic manipulations that control the signaling cascade, resulting in LIGHT production in conditions characterized by immunopathologic activation of T cells.
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页码:42841 / 42851
页数:11
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