Peroxisome proliferator-activated receptor-γ abrogates Smad-dependent collagen stimulation by targeting the p300 transcriptional coactivator

Asish K Ghosh, Swati Bhattacharyya, Jun Wei, Suyeon Kim, Yaacov Barak, Yasuji Mori, John Varga

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

Ligands of peroxisome proliferator-activated receptor-γ (PPAR-γ) abrogate the stimulation of collagen gene transcription induced by transforming growth factor-beta (TGF-β). Here, we delineate the mechanisms underlying this important novel physiological function for PPAR-γ in connective tissue homeostasis. First, we demonstrated that antagonistic regulation of TGF-β activity by PPAR-γ ligands involves cellular PPAR-γ, since 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) failed to block TGF-β-induced responses in either primary cultures of PPAR-γ-null murine embryonic fibroblasts, or in normal human skin fibroblasts with RNAi-mediated knockdown of PPAR-γ. Next, we examined the molecular basis underlying the abrogation of TGF-β signaling by PPAR-γ in normal human fibroblasts in culture. The results demonstrated that Smad-dependent transcriptional responses were blocked by PPAR-γ without preventing Smad2/3 activation. In contrast, the interaction between activated Smad2/3 and the transcriptional coactivator and histone acetyltransferase p300 induced by TGF-β, and the accumulation of p300 on consensus Smad-binding DNA sequences and histone H4 hyperacetylation at the COL1A2 locus, were all prevented by PPAR-γ. Wild-type p300, but not a mutant form of p300 lacking functional histone acetyltransferase, was able to restore TGF-β-induced stimulation of COL1A2 in the presence of PPAR-γ ligands. Collectively, these results indicate that PPAR-γ blocked Smad-mediated transcriptional responses by preventing p300 recruitment and histone H4 hyperacetylation, resulting in the inhibition of TGF-β-induced collagen gene expression. Pharmacological activation of PPAR-γ thus may represent a novel therapeutic approach to target p300-dependent TGF-β profibrotic responses such as stimulation of collagen gene expression.

Original languageEnglish (US)
Pages (from-to)2968-2977
Number of pages10
JournalFASEB Journal
Volume23
Issue number9
DOIs
StatePublished - Sep 1 2009

Fingerprint

Peroxisome Proliferator-Activated Receptors
Collagen
Transforming Growth Factor beta
Fibroblasts
Histone Acetyltransferases
Ligands
Cell culture
Gene expression
Histones
Tissue homeostasis
Chemical activation
Gene Expression
DNA sequences
Transcription
RNA Interference
Connective Tissue
Skin
Homeostasis
Genes

Keywords

  • 15d
  • Acetyltransferase
  • Fibroblast
  • Fibrosis
  • PGJ
  • Type I collagen

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

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title = "Peroxisome proliferator-activated receptor-γ abrogates Smad-dependent collagen stimulation by targeting the p300 transcriptional coactivator",
abstract = "Ligands of peroxisome proliferator-activated receptor-γ (PPAR-γ) abrogate the stimulation of collagen gene transcription induced by transforming growth factor-beta (TGF-β). Here, we delineate the mechanisms underlying this important novel physiological function for PPAR-γ in connective tissue homeostasis. First, we demonstrated that antagonistic regulation of TGF-β activity by PPAR-γ ligands involves cellular PPAR-γ, since 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) failed to block TGF-β-induced responses in either primary cultures of PPAR-γ-null murine embryonic fibroblasts, or in normal human skin fibroblasts with RNAi-mediated knockdown of PPAR-γ. Next, we examined the molecular basis underlying the abrogation of TGF-β signaling by PPAR-γ in normal human fibroblasts in culture. The results demonstrated that Smad-dependent transcriptional responses were blocked by PPAR-γ without preventing Smad2/3 activation. In contrast, the interaction between activated Smad2/3 and the transcriptional coactivator and histone acetyltransferase p300 induced by TGF-β, and the accumulation of p300 on consensus Smad-binding DNA sequences and histone H4 hyperacetylation at the COL1A2 locus, were all prevented by PPAR-γ. Wild-type p300, but not a mutant form of p300 lacking functional histone acetyltransferase, was able to restore TGF-β-induced stimulation of COL1A2 in the presence of PPAR-γ ligands. Collectively, these results indicate that PPAR-γ blocked Smad-mediated transcriptional responses by preventing p300 recruitment and histone H4 hyperacetylation, resulting in the inhibition of TGF-β-induced collagen gene expression. Pharmacological activation of PPAR-γ thus may represent a novel therapeutic approach to target p300-dependent TGF-β profibrotic responses such as stimulation of collagen gene expression.",
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Peroxisome proliferator-activated receptor-γ abrogates Smad-dependent collagen stimulation by targeting the p300 transcriptional coactivator. / Ghosh, Asish K; Bhattacharyya, Swati; Wei, Jun; Kim, Suyeon; Barak, Yaacov; Mori, Yasuji; Varga, John.

In: FASEB Journal, Vol. 23, No. 9, 01.09.2009, p. 2968-2977.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Peroxisome proliferator-activated receptor-γ abrogates Smad-dependent collagen stimulation by targeting the p300 transcriptional coactivator

AU - Ghosh, Asish K

AU - Bhattacharyya, Swati

AU - Wei, Jun

AU - Kim, Suyeon

AU - Barak, Yaacov

AU - Mori, Yasuji

AU - Varga, John

PY - 2009/9/1

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N2 - Ligands of peroxisome proliferator-activated receptor-γ (PPAR-γ) abrogate the stimulation of collagen gene transcription induced by transforming growth factor-beta (TGF-β). Here, we delineate the mechanisms underlying this important novel physiological function for PPAR-γ in connective tissue homeostasis. First, we demonstrated that antagonistic regulation of TGF-β activity by PPAR-γ ligands involves cellular PPAR-γ, since 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) failed to block TGF-β-induced responses in either primary cultures of PPAR-γ-null murine embryonic fibroblasts, or in normal human skin fibroblasts with RNAi-mediated knockdown of PPAR-γ. Next, we examined the molecular basis underlying the abrogation of TGF-β signaling by PPAR-γ in normal human fibroblasts in culture. The results demonstrated that Smad-dependent transcriptional responses were blocked by PPAR-γ without preventing Smad2/3 activation. In contrast, the interaction between activated Smad2/3 and the transcriptional coactivator and histone acetyltransferase p300 induced by TGF-β, and the accumulation of p300 on consensus Smad-binding DNA sequences and histone H4 hyperacetylation at the COL1A2 locus, were all prevented by PPAR-γ. Wild-type p300, but not a mutant form of p300 lacking functional histone acetyltransferase, was able to restore TGF-β-induced stimulation of COL1A2 in the presence of PPAR-γ ligands. Collectively, these results indicate that PPAR-γ blocked Smad-mediated transcriptional responses by preventing p300 recruitment and histone H4 hyperacetylation, resulting in the inhibition of TGF-β-induced collagen gene expression. Pharmacological activation of PPAR-γ thus may represent a novel therapeutic approach to target p300-dependent TGF-β profibrotic responses such as stimulation of collagen gene expression.

AB - Ligands of peroxisome proliferator-activated receptor-γ (PPAR-γ) abrogate the stimulation of collagen gene transcription induced by transforming growth factor-beta (TGF-β). Here, we delineate the mechanisms underlying this important novel physiological function for PPAR-γ in connective tissue homeostasis. First, we demonstrated that antagonistic regulation of TGF-β activity by PPAR-γ ligands involves cellular PPAR-γ, since 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) failed to block TGF-β-induced responses in either primary cultures of PPAR-γ-null murine embryonic fibroblasts, or in normal human skin fibroblasts with RNAi-mediated knockdown of PPAR-γ. Next, we examined the molecular basis underlying the abrogation of TGF-β signaling by PPAR-γ in normal human fibroblasts in culture. The results demonstrated that Smad-dependent transcriptional responses were blocked by PPAR-γ without preventing Smad2/3 activation. In contrast, the interaction between activated Smad2/3 and the transcriptional coactivator and histone acetyltransferase p300 induced by TGF-β, and the accumulation of p300 on consensus Smad-binding DNA sequences and histone H4 hyperacetylation at the COL1A2 locus, were all prevented by PPAR-γ. Wild-type p300, but not a mutant form of p300 lacking functional histone acetyltransferase, was able to restore TGF-β-induced stimulation of COL1A2 in the presence of PPAR-γ ligands. Collectively, these results indicate that PPAR-γ blocked Smad-mediated transcriptional responses by preventing p300 recruitment and histone H4 hyperacetylation, resulting in the inhibition of TGF-β-induced collagen gene expression. Pharmacological activation of PPAR-γ thus may represent a novel therapeutic approach to target p300-dependent TGF-β profibrotic responses such as stimulation of collagen gene expression.

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KW - PGJ

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