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Molecular and Cellular Biology, December 1998, p. 7157-7165, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Utilization of an NF-ATp Binding Promoter Element for EGR3 Expression in T Cells but Not Fibroblasts Provides a Molecular Model for the Lymphoid Cell-Specific Effect of Cyclosporin A

Hans W. Mages,* Rima Baag, Birgit Steiner, and Richard A. Kroczek

Molecular Immunology, Robert Koch-Institute, D-13353 Berlin, Germany

Received 17 June 1998/Returned for modification 12 August 1998/Accepted 9 September 1998

Cyclosporin A (CsA) mainly exerts its immunosuppressive action by selectively inhibiting Ca2+/calcineurin-dependent gene transcription in lymphoid cells. A model explaining the tissue-specific effect of this drug on gene expression has not been established to date, since none of the known intracellular targets of CsA (e.g., cyclophilins, calcineurin, and NF-AT) is lymphoid cell specific. To investigate this issue, we performed a detailed comparative analysis of the promoter regulating the two-signal-dependent (Ca2+ ionophore plus phorbol myristate acetate [PMA]), CsA-sensitive expression of EGR3 in T cells and the one-signal-dependent (PMA), CsA-insensitive expression of EGR3 in fibroblasts. As a result, we identified a 27-bp promoter element functionally interacting with transcription factors NF-ATp and NF-ATc that is crucial for the CsA-sensitive expression of the EGR3 gene in T cells. In contrast, the same element was without function in fibroblasts, and other, CsA-insensitive promoter regions were found to be responsible for EGR3 gene expression in these cells. The inactivity of the 27-bp element in fibroblasts was apparently due to insufficient expression levels of NF-ATp, since overexpression of NF-ATp, but not NF-ATc, restored the two-signal phenotype and CsA sensitivity of EGR3 promoter induction in these cells. The differential usage of an NF-AT binding site explains the selective effect of CsA on EGR3 gene expression in T cells versus fibroblasts and may represent one of the basic mechanisms underlying the tissue specificity of CsA.

* Corresponding author. Mailing address: Molecular Immunology, Robert Koch-Institute, Nordufer 20, D-13353 Berlin, Germany. Phone: 49-30-4547-2400. Fax: 49-30-4547-2603. E-mail: magesh{at}rki.de.

Molecular and Cellular Biology, December 1998, p. 7157-7165, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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