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
Department of Internal Medicine (Cardiology)
Department of Biochemistry
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.
https://doi.org/10.1210/me.2008-0101
Published - 2008 Dec
10.1210/me.2008-0101
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hexamethylene bisacetamide Medicine & Life Sciences
Glucocorticoid Receptors Medicine & Life Sciences
Glucocorticoids Medicine & Life Sciences
Hep G2 Cells Medicine & Life Sciences
Peptide Elongation Factors Medicine & Life Sciences
Pharmacological Phenomena Medicine & Life Sciences
Shimizu, N., Yoshikawa, N., Wada, T., Handa, H., Sano, M., Fukuda, K., Suematsu, M., Sawai, T., Morimoto, C., & Tanaka, H. (2008). Tissue- and context-dependent modulation of hormonal sensitivity of glucocorticoid-responsive genes by hexamethylene bisacetamide-inducible protein 1. Molecular Endocrinology, 22(12), 2609-2623. https://doi.org/10.1210/me.2008-0101
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.
Shimizu, N, Yoshikawa, N, Wada, T, Handa, H, Sano, M, Fukuda, K, Suematsu, M, Sawai, T, Morimoto, C & Tanaka, H 2008, 'Tissue- and context-dependent modulation of hormonal sensitivity of glucocorticoid-responsive genes by hexamethylene bisacetamide-inducible protein 1', Molecular Endocrinology, vol. 22, no. 12, pp. 2609-2623. https://doi.org/10.1210/me.2008-0101
Shimizu N, Yoshikawa N, Wada T, Handa H, Sano M, Fukuda K et al. Tissue- and context-dependent modulation of hormonal sensitivity of glucocorticoid-responsive genes by hexamethylene bisacetamide-inducible protein 1. Molecular Endocrinology. 2008 Dec;22(12):2609-2623. https://doi.org/10.1210/me.2008-0101
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.
@article{b599877737b04ccebe172c0ca9d2fc3a,
title = "Tissue- and context-dependent modulation of hormonal sensitivity of glucocorticoid-responsive genes by hexamethylene bisacetamide-inducible protein 1",
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.",
author = "Noriaki Shimizu and Noritada Yoshikawa and Tadashi Wada and Hiroshi Handa and Motoaki Sano and Keiichi Fukuda and Makoto Suematsu and Takashi Sawai and Chikao Morimoto and Hirotoshi Tanaka",
doi = "10.1210/me.2008-0101",
journal = "Molecular Endocrinology",
publisher = "The Endocrine Society",
T1 - Tissue- and context-dependent modulation of hormonal sensitivity of glucocorticoid-responsive genes by hexamethylene bisacetamide-inducible protein 1
AU - Shimizu, Noriaki
AU - Yoshikawa, Noritada
AU - Wada, Tadashi
AU - Handa, Hiroshi
AU - Sano, Motoaki
AU - Fukuda, Keiichi
AU - Suematsu, Makoto
AU - Sawai, Takashi
AU - Morimoto, Chikao
AU - Tanaka, Hirotoshi
N2 - 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.
AB - 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.
U2 - 10.1210/me.2008-0101
DO - 10.1210/me.2008-0101
JO - Molecular Endocrinology
JF - Molecular Endocrinology