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Tissue- and Context-Dependent Modulation of Hormonal Sensitivity of Glucocorticoid-Responsive Genes by Hexamethylene Bisacetamide-Inducible Protein 1

Division of Clinical Immunology (N.S., N.Y., C.M., H.T.), Advanced Clinical Research Center; Department of Rheumatology and Allergy (N.Y., C.M., H.T.), Research Hospital, Institute of Medical Science, University of Tokyo, Tokyo 108-8369, Japan; Department of Biological Information (T.W., H.H.), Graduate School of Bioscience and Biotechnology; Solutions Research Division (H.H.), Integrated Research Institute, Tokyo Institute of Technology, Yokohama 226-8501, Japan; Department of Regenerative Medicine and Advanced Cardiac Therapeutics (M.S., K.F.); Department of Biochemistry and Integrative Medical Biology (M.S.), Keio University School of Medicine, Tokyo 160-8582, Japan; and Department of Pathology I (T.S.), Iwate Medical University, Morioka 020-8505, Japan

Address all correspondence and requests for reprints to: Hirotoshi Tanaka, Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. E-mail: hirotnk{at}ims.u-tokyo.ac.jp.

Physiological and pharmacological processes mediated by glucocorticoids involve tissue- and context-specific regulation of glucocorticoid-responsive gene expression via glucocorticoid receptor (GR). However, the molecular mechanisms underlying such highly coordinated regulation of glucocorticoid actions remain to be studied. We here addressed this issue using atp1a1 and scnn1a, both of which are up-regulated in response to corticosteroids in human embryonic kidney-derived 293 cells, but resistant in liver-derived HepG2 cells. Hexamethylene bisacetamide-inducible protein 1 (HEXIM1) represses gene expression via, at least, two distinct mechanisms, i.e. positive transcription elongation factor b sequestration and direct interaction with GR, and is relatively high in HepG2 cells compared with 293 cells. Given this, we focused on the role of HEXIM1 in transcriptional regulation of these GR target genes. In HepG2 cells, hormone resistance of atp1a1 and scnn1a was diminished by either knockdown of HEXIM1 or overexpression of GR. Such a positive effect of exogenous expression of GR was counteracted by concomitant overexpression of HEXIM1, indicating the balance between GR and HEXIM1 modulates hormonal sensitivity of these genes. In support of this, the hormone-dependent recruitment of RNA polymerase II onto atp1a1 promoter was in parallel with that of GR. Moreover, we revealed that not positive transcription elongation factor b-suppressing activity but direct interaction with GR of HEXIM1 plays a major role in suppression of promoter recruitment of the receptor and subsequent atp1a1 and scnn1a gene activation. Collectively, we may conclude that HEXIM1 may participate in tissue-selective determination of glucocorticoid sensitivity via direct interaction with GR at least in certain gene sets including atp1a1 and scnn1a.

NURSA Molecule Pages Link:

Nuclear Receptors:   GR

Coregulators:   P-TEFb

Ligands:   Dexamethasone