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Nuclear Export of Glucocorticoid Receptor is Enhanced by c-Jun N-Terminal Kinase-Mediated Phosphorylation

First Department of Internal Medicine (M.I., M.A., H.Y., K.I.), Sapporo Medical University School of Medicine, Sapporo, 060-8543, Japan; and Division of Molecular Cell Signaling (M.T.), and Division of Clinical Immunology (H.T.), Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

Address all correspondence and requests for reprints to: Masaaki Adachi, First Department of Internal Medicine, Sapporo Medical University School of Medicine, S1 W16, Chuo-ku, Sapporo, 060-8543 Japan. E-mail: .

The c-Jun N-terminal kinase (JNK) phosphorylates the glucocorticoid receptor (GR) and inhibits GR-mediated transcription. However, the biological effect of the GR phosphorylation remains unknown. Here we demonstrate that activated JNK phosphorylates human GR at Ser226 and enhances its nuclear export after withdrawal of a ligand for GR, dexamethasone. At 1 h after dexamethasone withdrawal, green fluorescent protein-GR molecules were mostly retained at the nucleus, whereas UV exposure enhanced its nuclear export, and approximately 30–40% of cells revealed distinct nuclear export. JNK overexpression alone mimics UV exposure and enhanced GR export accompanied by inhibition of GR-mediated transcription. However, mutation of the Ser226 JNK phosphorylation site in GR abrogated UV-mediated enhancement of GR nuclear export. Furthermore, overexpression of a dominant negative SEK1 mutant also abrogated the effects of UV exposure on GR export. Taken together, these findings suggest that JNK-mediated phosphorylation of the GR-Ser226 enhances GR nuclear export and may contribute to termination of GR-mediated transcription.

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Nuclear Receptors:   GR

Ligands:   Dexamethasone

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