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© The Rockefeller University Press,
0021-9525/2000//1199 $5.00
The Journal of Cell Biology, Volume 150, Number 5,
, 2000 1199-1208
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Glucocorticoids Antagonize Ap-1 by Inhibiting the Activation/Phosphorylation of Jnk without Affecting Its Subcellular Distribution
amunoz{at}iib.uam.es
The immunosuppressive and antiinflammatory actions of glucocorticoid hormones are mediated by their transrepression of activating protein-1 (AP-1) and nuclear factor-kappa B (NF
B) 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
(TNF-
)–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-
–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-
–induced activation of AP-1 by causing the accumulation of inactive JNK without affecting its subcellular distribution.
Key Words: dexamethasone activating protein-1 tumor necrosis factor
c-Jun NH2-terminal kinase nuclear translocation
© 2000 The Rockefeller University Press
María Victoria González and Benilde Jiménez contributed equally to this work.Abbreviations used in this paper: AP-1, activating protein-1; Dex, dexamethasone; GR, glucocorticoid receptor; GRdim, GR mutant deficient in dimerization; GRwt, GR wild-type; Hsp70, heat shock protein 70; JNK, c-Jun NH2-terminal kinase; TNF-
, tumor necrosis factor-
.
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