Tissue- and context-dependent modulation of hormonal sensitivity of glucocorticoid-responsive genes by hexamethylene bisacetamide-inducible protein 1

Noriaki Shimizu, Noritada Yoshikawa, Tadashi Wada, Hiroshi Handa, Motoaki Sano, Keiichi Fukuda, Makoto Suematsu, Takashi Sawai, Chikao Morimoto, Hirotoshi Tanaka

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)2609-2623
Number of pages15
JournalMolecular Endocrinology
Volume22
Issue number12
DOIs
Publication statusPublished - 2008 Dec

Fingerprint

hexamethylene bisacetamide
Glucocorticoid Receptors
Glucocorticoids
Genes
Proteins
Hep G2 Cells
Peptide Elongation Factors
Transcription Factors
Hormones
Physiological Phenomena
Gene Expression
RNA Polymerase II

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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Tissue- and context-dependent modulation of hormonal sensitivity of glucocorticoid-responsive genes by hexamethylene bisacetamide-inducible protein 1. / Shimizu, Noriaki; Yoshikawa, Noritada; Wada, Tadashi; Handa, Hiroshi; Sano, Motoaki; Fukuda, Keiichi; Suematsu, Makoto; Sawai, Takashi; Morimoto, Chikao; Tanaka, Hirotoshi.

In: Molecular Endocrinology, Vol. 22, No. 12, 12.2008, p. 2609-2623.

Research output: Contribution to journalArticle

Shimizu, Noriaki ; Yoshikawa, Noritada ; Wada, Tadashi ; Handa, Hiroshi ; Sano, Motoaki ; Fukuda, Keiichi ; Suematsu, Makoto ; Sawai, Takashi ; Morimoto, Chikao ; Tanaka, Hirotoshi. / Tissue- and context-dependent modulation of hormonal sensitivity of glucocorticoid-responsive genes by hexamethylene bisacetamide-inducible protein 1. In: Molecular Endocrinology. 2008 ; Vol. 22, No. 12. pp. 2609-2623.
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