The Smad6-histone deacetylase 3 complex silences the transcriptional activity of the glucocorticoid receptor

Potential clinical implications

Takamasa Ichijo, Antonis Voutetakis, Ana P. Cotrim, Nisan Bhattachryya, Makiko Fujii, George P. Chrousos, Tomoshige Kino

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Glucocorticoids play pivotal roles in the maintenance of homeostasis but, when dysregulated, may also have deleterious effects. Smad6, one of the transforming growth factor β(TGFβ) family downstream transcription factors, interacts with the N-terminal domain of the glucocorticoid receptor (GR) through its Mad homology 2 domain and suppresses GR-mediated transcriptional activity in vitro. Adenovirus-mediated Smad6 overexpression inhibits glucocorticoid action in rat liver in vivo, preventing dexamethasone-induced elevation of blood glucose levels and hepatic mRNA expression of phosphoenolpyruvate carboxykinase, a well known rate-limiting enzyme of liver gluconeogenesis. Smad6 suppresses GR-induced transactivation by attracting histone deacetylase 3 to DNA-bound GR and by antagonizing acetylation of histone H3 and H4 induced by p160 histone acetyltransferase. These results indicate that Smad6 regulates glucocorticoid actions as a corepressor of the GR. From our results and known cross-talks between glucocorticoids and TGFβ family molecules, it appears that the anti-glucocorticoid actions of Smad6 may contribute to the neuroprotective, anticatabolic and pro-wound healing properties of the TGFβ family of proteins.

Original languageEnglish
Pages (from-to)42067-42077
Number of pages11
JournalJournal of Biological Chemistry
Volume280
Issue number51
DOIs
Publication statusPublished - 23 Dec 2005
Externally publishedYes

Fingerprint

Histone Deacetylases
Glucocorticoid Receptors
Glucocorticoids
Transforming Growth Factors
Liver
Histones
Histone Acetyltransferases
Acetylation
Co-Repressor Proteins
Phosphoenolpyruvate
Gluconeogenesis
Adenoviridae
Wound Healing
Dexamethasone
Transcriptional Activation
Blood Glucose
Rats
Homeostasis
Transcription Factors
Maintenance

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

The Smad6-histone deacetylase 3 complex silences the transcriptional activity of the glucocorticoid receptor : Potential clinical implications. / Ichijo, Takamasa; Voutetakis, Antonis; Cotrim, Ana P.; Bhattachryya, Nisan; Fujii, Makiko; Chrousos, George P.; Kino, Tomoshige.

In: Journal of Biological Chemistry, Vol. 280, No. 51, 23.12.2005, p. 42067-42077.

Research output: Contribution to journalArticle

Ichijo, Takamasa ; Voutetakis, Antonis ; Cotrim, Ana P. ; Bhattachryya, Nisan ; Fujii, Makiko ; Chrousos, George P. ; Kino, Tomoshige. / The Smad6-histone deacetylase 3 complex silences the transcriptional activity of the glucocorticoid receptor : Potential clinical implications. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 51. pp. 42067-42077.
@article{ded2c5dcd5974331aa69759d73561c4a,
title = "The Smad6-histone deacetylase 3 complex silences the transcriptional activity of the glucocorticoid receptor: Potential clinical implications",
abstract = "Glucocorticoids play pivotal roles in the maintenance of homeostasis but, when dysregulated, may also have deleterious effects. Smad6, one of the transforming growth factor β(TGFβ) family downstream transcription factors, interacts with the N-terminal domain of the glucocorticoid receptor (GR) through its Mad homology 2 domain and suppresses GR-mediated transcriptional activity in vitro. Adenovirus-mediated Smad6 overexpression inhibits glucocorticoid action in rat liver in vivo, preventing dexamethasone-induced elevation of blood glucose levels and hepatic mRNA expression of phosphoenolpyruvate carboxykinase, a well known rate-limiting enzyme of liver gluconeogenesis. Smad6 suppresses GR-induced transactivation by attracting histone deacetylase 3 to DNA-bound GR and by antagonizing acetylation of histone H3 and H4 induced by p160 histone acetyltransferase. These results indicate that Smad6 regulates glucocorticoid actions as a corepressor of the GR. From our results and known cross-talks between glucocorticoids and TGFβ family molecules, it appears that the anti-glucocorticoid actions of Smad6 may contribute to the neuroprotective, anticatabolic and pro-wound healing properties of the TGFβ family of proteins.",
author = "Takamasa Ichijo and Antonis Voutetakis and Cotrim, {Ana P.} and Nisan Bhattachryya and Makiko Fujii and Chrousos, {George P.} and Tomoshige Kino",
year = "2005",
month = "12",
day = "23",
doi = "10.1074/jbc.M509338200",
language = "English",
volume = "280",
pages = "42067--42077",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "51",

}

TY - JOUR

T1 - The Smad6-histone deacetylase 3 complex silences the transcriptional activity of the glucocorticoid receptor

T2 - Potential clinical implications

AU - Ichijo, Takamasa

AU - Voutetakis, Antonis

AU - Cotrim, Ana P.

AU - Bhattachryya, Nisan

AU - Fujii, Makiko

AU - Chrousos, George P.

AU - Kino, Tomoshige

PY - 2005/12/23

Y1 - 2005/12/23

N2 - Glucocorticoids play pivotal roles in the maintenance of homeostasis but, when dysregulated, may also have deleterious effects. Smad6, one of the transforming growth factor β(TGFβ) family downstream transcription factors, interacts with the N-terminal domain of the glucocorticoid receptor (GR) through its Mad homology 2 domain and suppresses GR-mediated transcriptional activity in vitro. Adenovirus-mediated Smad6 overexpression inhibits glucocorticoid action in rat liver in vivo, preventing dexamethasone-induced elevation of blood glucose levels and hepatic mRNA expression of phosphoenolpyruvate carboxykinase, a well known rate-limiting enzyme of liver gluconeogenesis. Smad6 suppresses GR-induced transactivation by attracting histone deacetylase 3 to DNA-bound GR and by antagonizing acetylation of histone H3 and H4 induced by p160 histone acetyltransferase. These results indicate that Smad6 regulates glucocorticoid actions as a corepressor of the GR. From our results and known cross-talks between glucocorticoids and TGFβ family molecules, it appears that the anti-glucocorticoid actions of Smad6 may contribute to the neuroprotective, anticatabolic and pro-wound healing properties of the TGFβ family of proteins.

AB - Glucocorticoids play pivotal roles in the maintenance of homeostasis but, when dysregulated, may also have deleterious effects. Smad6, one of the transforming growth factor β(TGFβ) family downstream transcription factors, interacts with the N-terminal domain of the glucocorticoid receptor (GR) through its Mad homology 2 domain and suppresses GR-mediated transcriptional activity in vitro. Adenovirus-mediated Smad6 overexpression inhibits glucocorticoid action in rat liver in vivo, preventing dexamethasone-induced elevation of blood glucose levels and hepatic mRNA expression of phosphoenolpyruvate carboxykinase, a well known rate-limiting enzyme of liver gluconeogenesis. Smad6 suppresses GR-induced transactivation by attracting histone deacetylase 3 to DNA-bound GR and by antagonizing acetylation of histone H3 and H4 induced by p160 histone acetyltransferase. These results indicate that Smad6 regulates glucocorticoid actions as a corepressor of the GR. From our results and known cross-talks between glucocorticoids and TGFβ family molecules, it appears that the anti-glucocorticoid actions of Smad6 may contribute to the neuroprotective, anticatabolic and pro-wound healing properties of the TGFβ family of proteins.

UR - http://www.scopus.com/inward/record.url?scp=29644434851&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=29644434851&partnerID=8YFLogxK

U2 - 10.1074/jbc.M509338200

DO - 10.1074/jbc.M509338200

M3 - Article

VL - 280

SP - 42067

EP - 42077

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 51

ER -