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Molecular and Cellular Biology, March 2000, p. 2239-2247, Vol. 20, No. 6
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Stimulus-Specific Assembly of Enhancer Complexes on the Tumor Necrosis Factor Alpha Gene Promoterdagger

James V. Falvo,1 Adele M. Uglialoro,2 Brigitta M. N. Brinkman,2 Menie Merika,3 Bhavin S. Parekh,1 Eunice Y. Tsai,2 Hadley C. King,2 Anthony D. Morielli,1 Ernest G. Peralta,1,Dagger Tom Maniatis,1 Dimitris Thanos,3 and Anne E. Goldfeld2,*

Center for Blood Research and Harvard Medical School, Boston, Massachusetts 021152; Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 021381; Department of Biochemistry and Biophysics, Columbia University, New York, New York 100683

Received 26 October 1999/Returned for modification 29 November 1999/Accepted 6 December 1999

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.

* Corresponding author. Mailing address: Center for Blood Research, 800 Huntington Ave., Boston, MA 02115. Phone: (617) 278-3351. Fax: (617) 278-3454. E-mail: goldfeld{at}cbr.med.harvard.edu.

dagger Dedicated to the memory of Mauricio X. Zuber and Ernest G. Peralta.

Dagger Deceased 17 May 1999.

Molecular and Cellular Biology, March 2000, p. 2239-2247, Vol. 20, No. 6
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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