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

89 Scopus citations

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

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Keywords

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

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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