Peroxisome proliferator-activated receptor-gamma abrogates Smad-dependent collagen stimulation by targeting the p300 transcriptional coactivator.
Ligands of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) abrogate the stimulation of collagen gene transcription induced by transforming growth factor-beta (TGF-beta). Here, we delineate the mechanisms underlying this important novel physiological function for PPAR-gamma in connective tissue homeostasis. First, we demonstrated that antagonistic regulation of TGF-beta activity by PPAR-gamma ligands involves cellular PPAR-gamma, since 15-deoxy-Delta12,14-prostaglandin J(2) (15d-PGJ(2)) failed to block TGF-beta-induced responses in either primary cultures of PPAR-gamma-null murine embryonic fibroblasts, or in normal human skin fibroblasts with RNAi-mediated knockdown of PPAR-gamma. Next, we examined the molecular basis underlying the abrogation of TGF-beta signaling by PPAR-gamma in normal human fibroblasts in culture. The results demonstrated that Smad-dependent transcriptional responses were blocked by PPAR-gamma without preventing Smad2/3 activation. In contrast, the interaction between activated Smad2/3 and the transcriptional coactivator and histone acetyltransferase p300 induced by TGF-beta, and the accumulation of p300 on consensus Smad-binding DNA sequences and histone H4 hyperacetylation at the COL1A2 locus, were all prevented by PPAR-gamma. Wild-type p300, but not a mutant form of p300 lacking functional histone acetyltransferase, was able to restore TGF-beta-induced stimulation of COL1A2 in the presence of PPAR-gamma ligands. Collectively, these results indicate that PPAR-gamma blocked Smad-mediated transcriptional responses by preventing p300 recruitment and histone H4 hyperacetylation, resulting in the inhibition of TGF-beta-induced collagen gene expression. Pharmacological activation of PPAR-gamma thus may represent a novel therapeutic approach to target p300-dependent TGF-beta profibrotic responses such as stimulation of collagen gene expression.
Ghosh
Asish K
AK
Feinberg Cardiovascular Research Institute, Chicago, IL 60611, USA. a-ghosh2@northwestern.edu
Bhattacharyya
Swati
S
Wei
Jun
J
Kim
Suyeon
S
Barak
Yaacov
Y
Mori
Yasuji
Y
Varga
John
J
D000107:Acetylation; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D047495:PPAR gamma / Q000502:physiology*; D021381:Protein Transport; D051785:Smad Proteins / Q000502:physiology*; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000502:physiology; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
D003094:Collagen; D006657:Histones; D047495:PPAR gamma; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor