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Molecular and Cellular Biology, November 2002, p. 7929-7941, Vol. 22, No. 22
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.22.7929-7941.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Glucocorticoid-Induced Leucine Zipper Inhibits the Raf-Extracellular Signal-Regulated Kinase Pathway by Binding to Raf-1

Emira Ayroldi,1 Ornella Zollo,1 Antonio Macchiarulo,2 Barbara Di Marco,1 Cristina Marchetti,1 and Carlo Riccardi1*

Department of Clinical and Experimental Medicine, Section of Pharmacology,1 Department of Drug Chemistry and Technology, University of Perugia, 06100 Perugia, Italy2

Received 14 March 2002/ Returned for modification 15 April 2002/ Accepted 12 August 2002

Glucocorticoid-induced leucine zipper (GILZ) is a leucine zipper protein, whose expression is augmented by dexamethasone (DEX) treatment and downregulated by T-cell receptor (TCR) triggering. Stable expression of GILZ in T cells mimics some of the effects of glucocorticoid hormones (GCH) in GCH-mediated immunosuppressive and anti-inflammatory activity. In fact, GILZ overexpression inhibits TCR-activated NF-{kappa}B nuclear translocation, interleukin-2 production, FasL upregulation, and the consequent activation-induced apoptosis. We have investigated the molecular mechanism underlying GILZ-mediated regulation of T-cell activation by analyzing the effects of GILZ on the activity of mitogen-activated protein kinase (MAPK) family members, including Raf, MAPK/extracellular signal-regulated kinase (ERK) 1/2 (MEK-1/2), ERK-1/2, and c-Jun NH2-terminal protein kinase (JNK). Our results indicate that GILZ inhibited Raf-1 phosphorylation, which resulted in the suppression of both MEK/ERK-1/2 phosphorylation and AP-1-dependent transcription. We demonstrate that GILZ interacts in vitro and in vivo with endogenous Raf-1 and that Raf-1 coimmunoprecipitated with GILZ in murine thymocytes treated with DEX. Mapping of the binding domains and experiments with GILZ mutants showed that GILZ binds the region of Raf interacting with Ras through the NH2-terminal region. These data suggest that GILZ contributes, through protein-to-protein interaction with Raf-1 and the consequent inhibition of Raf-MEK-ERK activation, to regulating the MAPK pathway and to providing a further mechanism underlying GCH immunosuppression.

* Corresponding author. Mailing address: Section of Pharmacology, Department of Clinical and Experimental Medicine, Via del Giochetto, 06100 Perugia, Italy. Phone: 39-075-5857467. Fax: 39-075-5857405. E-mail: riccardi{at}unipg.it.

Molecular and Cellular Biology, November 2002, p. 7929-7941, Vol. 22, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.22.7929-7941.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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