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

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.