Open AccessStimulus-Specific Assembly of Enhancer Complexes on the Tumor Necrosis Factor Alpha Gene Promoter
Author(s) -
James V. Falvo,
Adele M. Uglialoro,
Brigitta M. N. Brinkman,
Menie Merika,
Bhavin S. Parekh,
Eunice Y. Tsai,
Hadley C. King,
Anthony D. Morielli,
Ernest G. Peralta,
Tom Maniatis,
Dimitris Thanos,
Anne E. Goldfeld
Publication year - 2000
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.20.6.2239-2247.2000
Subject(s) - nfat , enhancer , biology , tumor necrosis factor alpha , transcription factor , promoter , microbiology and biotechnology , reporter gene , gene expression , gene , immunology , genetics
The human tumor necrosis factor alpha (TNF-α) gene is rapidly activated in response to multiple signals of stress and inflammation. We have identified transcription factors present in the TNF-α 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-α gene transcription and selectively associates with the TNF-α promoter upon virus infection but not upon ionophore stimulation in vivo. We conclude that the specificity of TNF-α transcriptional activation is achieved through the assembly of stimulus-specific enhancer complexes and through synergistic interactions among the distinct activators within these enhancer complexes.