Effects of glucocorticoids on gene transcription

Hayashi, Ryuji; Wada, Hiroo; Ito, Kazuhiro; Adcock, Ian M.

doi:10.1016/j.ejphar.2004.07.011

Cited by 239 publications

(169 citation statements)

References 77 publications

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“…Once activated by GCs, GRs forms homodimers and translocate into the nucleus, where they ultimately bind to specific GRE on gene promoters to regulate transcription (Hayashi et al 2004, Smoak & Cidlowski 2004. However, this mechanism dose not explains all the actions of GCs.…”

Section: Discussionmentioning

confidence: 99%

“…However, this mechanism dose not explains all the actions of GCs. Several studies demonstrated that interaction of GR with other transcription factors could provide an alternative pathway for GC actions (Hayashi et al 2004, Smoak & Cidlowski 2004. GCs have been found to induce C/EBPa or C/EBPb expression in a number of tissues or cells (Zilberfarb et al 2001, Hernandez et al 2003, Yang et al 2005a.…”

Section: Discussionmentioning

confidence: 99%

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Role of glucocorticoid receptor and CCAAT/enhancer-binding protein α in the feed-forward induction of 11β-hydroxysteroid dehydrogenase type 1 expression by cortisol in human amnion fibroblasts

Yang¹,

Guo²,

Zhu³

et al. 2007

Journal of Endocrinology

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The amount of cortisol available to its receptors is increased by the pre-receptor enzyme 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) which converts cortisone to cortisol. We examined the molecular mechanisms of the feedback effect of cortisol on 11b-HSD1 mRNA expression in human amnion fibroblasts. Our data showed that cortisol-induced 11b-HSD1 mRNA expression dose dependently in amnion fibroblasts, which could be completely blocked both by the mRNA transcription inhibitor 5,6-dichlorobenzimidazole riboside and by the glucocorticoid receptor (GR) antagonist RU486, and partially blocked by global inhibition of CCAAT/enhancerbinding proteins (C/EBPs) with transfection of C/EBP-specific dominant-negative expression CMV500 plasmid (AC/EBP) into the cells. Likewise, the induction of the promoter activity by cortisol could also be completely blocked by RU486 and partially by AC/EBP transfection. Progressive 5 0 deletion of the 11b-HSD1 promoter located the region responsible for cortisol's induction within K204 bp upstream to the transcription start site. Specific nucleotide mutations of the putative glucocorticoid responsive element or CCAAT in this promoter region attenuated the induction by cortisol. Moreover, chromatin immunoprecipitation assay and electrophoretic mobility shift assay showed that GR and C/EBPa but not C/EBPb could bind this promoter region upon cortisol stimulation of amnion fibroblasts. In conclusion, we demonstrated that GR and C/EBPa were involved in cortisol-induced 11b-HSD1 mRNA expression via binding to 11b-HSD1 promoter in amnion fibroblasts, which may cast a feed-forward production of cortisol in the fetal membranes at the end of gestation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Role of glucocorticoid receptor and CCAAT/enhancer-binding protein α in the feed-forward induction of 11β-hydroxysteroid dehydrogenase type 1 expression by cortisol in human amnion fibroblasts

Yang¹,

Guo²,

Zhu³

et al. 2007

Journal of Endocrinology

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“…Unliganded GR has been shown to reside in the cytoplasm in association with chaperone complexes and to translocate into the nucleus upon binding of agonists to activate or transrepress gene expression at select promoters (2). The GR is widely expressed in a variety of cells and is involved in the regulation of immune responses, metabolism, and development (3).…”

mentioning

confidence: 99%

Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue

Mueller

2016

Proc. Natl. Acad. Sci. U.S.A.

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Glucocorticoids (GCs) are widely prescribed anti-inflammatory agents, but their chronic use leads to undesirable side effects such as excessive expansion of adipose tissue. We have recently shown that the forkhead box protein A3 (Foxa3) is a calorie-hoarding factor that regulates the selective enlargement of epididymal fat depots and suppresses energy expenditure in a nutritional- and age-dependent manner. It has been demonstrated that Foxa3 levels are elevated in adipose depots in response to high-fat diet regimens and during the aging process; however no studies to date have elucidated the mechanisms that control Foxa3’s expression in fat. Given the established effects of GCs in increasing visceral adiposity and in reducing thermogenesis, we assessed the existence of a possible link between GCs and Foxa3. Computational prediction analysis combined with molecular studies revealed that Foxa3 is regulated by the glucocorticoid receptor (GR) in preadipocytes, adipocytes, and adipose tissues and is required to facilitate the binding of the GR to its target gene promoters in fat depots. Analysis of the long-term effects of dexamethasone treatment in mice revealed that Foxa3 ablation protects mice specifically against fat accretion but not against other pathological side effects elicited by this synthetic GC in tissues such as liver, muscle, and spleen. In conclusion our studies provide the first demonstration, to our knowledge, that Foxa3 is a direct target of GC action in adipose tissues and point to a role of Foxa3 as a mediator of the side effects induced in fat tissues by chronic treatment with synthetic steroids.

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“…According to this transcriptional (genomic) model of action, the lipophilic corticosteroid molecules cross the cell membrane and bind to intracellular glucocorticoid receptors, which ultimately alter transcription through direct DNA binding (transactivation) [5] or bythe inactivation of pro-inflammatory transcription factors (transrepression) [6] such as nuclear factor-κB [7] and activating protein-1 [8].…”

Section: Introductionmentioning

confidence: 99%