Stimulus-specific assembly of enhancer complexes on the tumor necrosis factor alpha gene promoter

被引:141
作者
Falvo, JV
Uglialoro, AM
Brinkman, BMN
Merika, M
Parekh, BS
Tsai, EY
King, HC
Morielli, AD
Peralta, EG
Maniatis, T
Thanos, D
Goldfeld, AE
机构
[1] Ctr Blood Res, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Boston, MA 02115 USA
[3] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA
[4] Columbia Univ, Dept Biochem & Biophys, New York, NY 10068 USA
关键词
D O I
10.1128/MCB.20.6.2239-2247.2000
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
The human tumor necrosis factor alpha (TNF-alpha) gene is rapidly activated in response to multiple signals of stress and inflammation. We have identified transcription factors present in the TNF-alpha enhancer complex in vivo following ionophore stimulation (ATF-2/Jun and NFAT) and virus infection (ATF-2/Jun, NFAT, and Sp1), demonstrating a novel role for NFAT and Sp1 in virus induction of gene expression. We show that virus infection results in calcium flux and calcineurin-dependent NFAT dephosphorylation; however, relatively lower levels of NFAT are present in the nucleus following virus infection as compared to ionophore stimulation. Strikingly, Sp1 functionally synergizes with NFAT and ATF-2/c-jun in the activation of TNF-alpha gene transcription and selectively associates with the TNF-alpha promoter upon virus infection but not upon ionophore stimulation in vivo. We conclude that the specificity of TNF-alpha transcriptional activation is achieved through the assembly of stimulus-specific enhancer complexes and through synergistic interactions among the distinct activators within these enhancer complexes.
引用
收藏
页码:2239 / 2247
页数:9
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