Stimulus-specific assembly of enhancer complexes on the tumor necrosis factor alpha gene promoter.
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.
Falvo
J V
JV
Department of Molecular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Uglialoro
A M
AM
Brinkman
B M
BM
Merika
M
M
Parekh
B S
BS
Tsai
E Y
EY
King
H C
HC
Morielli
A D
AD
Peralta
E G
EG
Maniatis
T
T
Thanos
D
D
Goldfeld
A E
AE
D004268:DNA-Binding Proteins / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics; D006801:Humans; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha