Nucleic Acids Research, 2003, Vol. 31, No. 3 911-921
© 2003 Oxford University Press
Early growth response proteins (EGR) and nuclear factors of activated T cells (NFAT) form heterodimers and regulate proinflammatory cytokine gene expression
Research Group of Biomolecular Medicine, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Bernhard-Nocht Strasse 74, Germany, 1 Department of Infection Biology, Hans-Knoell-Institute for Natural Products Research, Beutenbergstrasse 11a, 07745 Jena, Germany and 2 Research Group of Rheumatology, Albert-Ludwig-University, Hugstetter Strasse 55, 79106 Freiburg, Germany
*To whom correspondence should be addressed. Tel: +49 3641 656848; Fax: +49 3641 656902; Email: cskerka{at}pmail.hki-jena.de
Present address:
Eva L. Decker, Institute Biology II, Albert-Ludwig-University, Schaenzle Strasse 1, 79104 Freiburg, Germany
Activation of transcription factors by receptor mediated signaling is an essential step for T lymphocyte effector function. Following antigenic stimulation of T cells the two central cytokines IL-2 and TNF
are co-expressed and co-regulated. Two important transcription factors, i.e., early growth response (EGR) protein EGR-1 and nuclear factors of activated T cells (NFAT) protein NFATc, regulate transcription of the human IL-2 cytokine and the same combination of EGR and NFAT proteins seems relevant for coordinated cytokine expression. Here we demonstrate that the zinc finger protein EGR-1 and two members of the NFAT protein family bind simultaneously to adjacent elements position –168 to –150 within the TNF promoter. Both promoter sites are important for TNF gene transcription as shown by transfection assays having the IL-2 and TNF promoters linked to a luciferase reporter. The use of promoter deletion constructs with the zinc finger protein (ZIP), the NFAT binding element or a combination of both deleted show a functional cooperation of these elements and of their binding factors. These experiments demonstrate that EGR-1 as well as EGR-4 functionally cooperate with NFAT proteins and induce expression of both cytokine genes. Using tagged NFATc and NFATp in glutathione S-transferase pull down assays showed interaction and physical complex formation of each NFAT protein with recombinant, as well as native, EGR-1 and EGR-4 proteins. Thus EGR-NFAT interaction and complex formation seems essential for human cytokine expression as adjacent ZIP and NFAT elements are conserved in the IL-2 and TNF gene promoters. Binding of regulatory EGR and NFAT factors to these sites and the functional interaction and formation of stable heterodimeric complexes indicate an important role of these factors for gene transcription.
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