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PMID: 14609950 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Glucocorticoid receptor-JNK interaction mediates inhibition of the JNK pathway by glucocorticoids.

The EMBO journal ·Vol. 22 ·No. 22 ·2003-11-17 ·Pages 6035-44

Bruna A, Nicolàs M, Muñoz A, Kyriakis JM, Caelles C

Abstract

Inhibition of the c-Jun N-terminal kinase (JNK) pathway by glucocorticoids (GCs) results in AP-1 repression. GC antagonism of AP-1 relies mainly on the transrepression function of the GC receptor (GR) and mediates essential physiological and pharmacological actions. Here we show that GCs induce the disassembly of JNK from mitogen-activated protein kinase kinase 7 (MKK7) by promoting its association with GR. Moreover, we have characterized a hormone-regulated JNK docking site in the GR ligand-binding domain that mediates GR-JNK interaction. The binding of GR to JNK is required for inhibition of JNK activation and induction of inactive JNK nuclear transfer by GCs. The dissociation of these two hormone actions shows that JNK nuclear transfer is dispensable for the downregulation of JNK activation by GCs. Nonetheless, nuclear accumulation of inactive JNK may still be relevant for enhancing the repression of AP-1 activity by GCs. In this regard, chromatin immunoprecipitation assays show that GC-induced GR-JNK association correlates with an increase in the loading of inactive JNK on the AP-1-bound response elements of the c-jun gene.

MeSH Terms
Animals Binding Sites COS Cells Cell Nucleus/metabolism Chlorocebus aethiops Glucocorticoids/metabolism HeLa Cells Humans JNK Mitogen-Activated Protein Kinases MAP Kinase Kinase 7 Mitogen-Activated Protein Kinase Kinases/metabolism Mitogen-Activated Protein Kinases/genetics,metabolism Receptors, Glucocorticoid/metabolism Transcription Factor AP-1/metabolism
Chemicals
Glucocorticoids Receptors, Glucocorticoid Transcription Factor AP-1 JNK Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinases MAP Kinase Kinase 7 MAP2K7 protein, human Mitogen-Activated Protein Kinase Kinases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Bruna Alejandra
Institut de Recerca Biomèdica de Barcelona-Parc Científic de Barcelona (IRBB-PCB), Department of Bioquímica i Biologia Molecular, Universitat de Barcelona, E-08028 Barcelona, Spain.
Nicolàs Marta
Muñoz Alberto
Kyriakis John M
Caelles Carme
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/cdg590
Published
2003-11-17
Pages
6035-44
Language
English
Region
England
NLM ID
8208664
PMCID
PMC275446
Subset
IM
External Links
PubMed source DOI: 10.1093/emboj/cdg590 PMC Full Text View journal details
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