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  • The EMBO Journal (2003) 22, 6035 - 6044
  • doi:10.1093/emboj/cdg590

Glucocorticoid receptor–JNK interaction mediates inhibition of the JNK pathway by glucocorticoids

Alejandra Bruna1,5, Marta Nicolàs2,5, Alberto Muñoz3, John M Kyriakis4 and Carme Caelles2

  1. Present address: Derald H.Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, NY 10029, USA
  2. Institut de Recerca Biomèdica de Barcelona-Parc Científic de Barcelona (IRBB-PCB) and Departament de Bioquímica i Biologia Molecular, Divisió IV, Universitat de Barcelona, E-08028 Barcelona
  3. Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, E-28029-Madrid, Spain
  4. Molecular Cardiology Research Institute, New England Medical Center, Boston, MA 02111, USA
  5. A.Bruna and M.Nicolàs contributed equally to this work

Correspondence to:

Carme Caelles, E-mail: ccaelles@pcb.ub.es

Received 27 March 2003; Accepted 2 October 2003; Revised 16 September 2003

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.

  • Keywords:

    • AP-1 antagonism,
    • cell signaling,
    • cross-talk,
    • MAPK docking site,
    • MAPK pathway