The DNA Binding-independent Function of the Glucocorticoid Receptor Mediates Repression of AP-1-dependent Genes in Skin

doi:10.1083/jcb.147.7.1365

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© The Rockefeller University Press, 0021-9525/1999/12/1365/ $5.00
The Journal of Cell Biology, Volume 147, Number 7, December 27, 1999 1365-1370

Brief Report

The DNA Binding-independent Function of the Glucocorticoid Receptor Mediates Repression of AP-1–dependent Genes in Skin

Jan P. Tuckermann^a, Holger M. Reichardt^b, Rosa Arribas^b, K. Hartmut Richter^a, Günther Schütz^b, and Peter Angel^a
^a Division of Signal Transduction and Growth Control, Deutsches Krebsforschungszentrum, D-69120 Heidelberg, Germany
^b Division of Molecular Biology of the Cell I, Deutsches Krebsforschungszentrum, D-69120 Heidelberg, Germany

Correspondence to: Peter Angel, Division of Signal Transduction and Growth Control, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. Tel:49 6221-42-4570 Fax:49 6221-42-4554 E-mail:p.angel{at}dkfz-heidelberg.de.

The glucocorticoid receptor (GR) mediates the biological effectsof glucocorticoids (GCs) through activation or repression ofgene expression, either by DNA binding or via interaction withother transcription factors, such as AP-1. Work in tissue culturecells on the regulation of AP-1–dependent genes, suchas collagenase (MMP-13) and stromelysin (MMP-3) has suggestedthat the antitumor and antiinflammatory activity of GCs is mediated,at least in part, by GR-mediated downmodulation of AP-1. Here,we have identified phorbol ester-induced expression of MMP-3and MMP-13 in mouse skin as the first example of an in vivosystem to measure negative interference between AP-1 and GRin the animal. Cell type-specific induction of these genes bytumor promoters is abolished by GCs. Importantly, this is alsothe case in GR^dim mice expressing a DNA binding-defective mutantversion of GR. In contrast, the newly identified target genesin skin, plasma glutathione peroxidase and HSP-27, were inducedby GC in wild-type, but not in GR^dim mice. Thus, these datasuggest that the DNA binding-independent function of the GRis dispensable for repression of AP-1 activity in vivo and responsiblefor the antitumor promoting activity of GCs.

Key Words: tumor promotion, mouse skin, AP-1, matrix metalloproteinase,collagenase, glucocorticoid receptor, GR^dim

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