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Glucocorticoids antagonize Ap-1 by inhibiting the activation/phosphorylation of Jnk without affecting its subcellular distribution

AuthorsGonzález, María Victoria; Jiménez, Benilde ; Berciano, María T.; González-Sancho, José Manuel ; Caelles, Carme; Lafarga, Miguel; Muñoz Terol, Alberto
Activating protein-1
Tumor necrosis factor α
c-Jun NH2-terminal kinase
Nuclear translocation
Issue Date4-Sep-2000
PublisherRockefeller University Press
CitationJournal of Cell Biology 150(5): 1199–1208 (2000)
AbstractThe immunosuppressive and antiinflammatory actions of glucocorticoid hormones are mediated by their transrepression of activating protein-1 (AP-1) and nuclear factor-kappa B (NFκB) transcription factors. Inhibition of the c-Jun NH2-terminal kinase (JNK) signaling pathway, the main mediator of AP-1 activation, has been described in extracts of hormone-treated cells. Here, we show by confocal laser microscopy, enzymatic assays, and immunoblotting that the synthetic glucocorticoid dexamethasone inhibited tumor necrosis factor α (TNF-α)–induced phosphorylation and activation of JNK in the cytoplasm and nucleus of intact HeLa cells. As a result, c-Jun NH2-terminal domain phosphorylation and induction were impaired. Dexamethasone did not block the TNF-α–induced JNK nuclear translocation, but rather induced, per se, nuclear accumulation of the enzyme. Consistently with previous findings, a glucocorticoid receptor mutant (GRdim), which is deficient in dimerization, DNA binding, and transactivation, but retains AP-1 transrepressing activity, was as efficient as wild-type GR in mediating the same effects of dexamethasone on JNK in transfected Cos-7 cells. Our results show that glucocorticoids antagonize the TNF-α–induced activation of AP-1 by causing the accumulation of inactive JNK without affecting its subcellular distribution.
Publisher version (URL)http://dx.doi.org/10.1083/jcb.150.5.1199
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