Cytosolic Regulation of JNK by Glucocorticoid Receptors

Abstract

Although the glucocorticoid receptor (GR) is a member of the nuclear receptor family of ligand-activated transcription factors, some effects of glucocorticoids occur in the absence of DNA binding and without requiring glucocorticoid-stimulated gene expression. Bruna et al. show that the glucocorticoids stimulate a direct interaction (coimmunoprecipitation and glutathione S -transferase pull-down assays) between the GR and c-Jun N-terminal kinase (JNK), which decreased the interaction between JNK and its activating kinase MKK7. A mitogen-activated protein kinase docking motif in the ligand-binding domain of GR, a sequence that is uniquely present in the GR out of all of the other members of the nuclear receptor family, was responsible for the ligand-stimulated disruption of interaction of GR and JNK. Mutants of the GR that could not interact with JNK did not mediate glucocorticoid inhibition of JNK protein kinase activity stimulated by tumor necrosis factor-α. Mutants of the GR that could not dimerize (GR dim ) or be transported to the nucleus (and were thus inactive for stimulation of gene expression) still interacted with JNK and inhibited its kinase activity in the cytoplasm. However, interaction with the GR normally stimulates nuclear accumulation of JNK. Indeed, association of inactive GR-associated JNK with the c-jun promoter appears to contribute to the inhibition of the function of the transcription factor AP-1. Thus, inhibition of JNK signaling by glucocorticoids appears to be mediated in the cytosol through a direct interaction with the GR, and subsequent translocation of inactive JNK to the nucleus by association with the GR may contribute to gene transrepression activity. A. Bruna, M. Nicolàs, A. Muñoz, J. M. Kyriakis, C. Caelles, Glucocorticoid receptor-JNK interaction mediates inhibition of the JNK pathway by glucocorticoids. EMBO J. 22 , 6035-6044 (2003). [Abstract] [Full Text]