PubMed:19395477 JSONTXT

{"project":"PMID_GLOBAL","denotations":[{"id":"T1","span":{"begin":789,"end":793},"obj":"DiseaseOrPhenotypicFeature"}],"attributes":[{"id":"A1","pred":"mondo_id","subj":"T1","obj":"0002531"}],"text":"Peroxisome proliferator-activated receptor-gamma abrogates Smad-dependent collagen stimulation by targeting the p300 transcriptional coactivator.\nLigands 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."}

{"project":"bionlp-st-epi-2011-training","denotations":[{"id":"T1","span":{"begin":0,"end":48},"obj":"Protein"},{"id":"T2","span":{"begin":112,"end":116},"obj":"Protein"},{"id":"T3","span":{"begin":157,"end":205},"obj":"Protein"},{"id":"T4","span":{"begin":207,"end":217},"obj":"Protein"},{"id":"T5","span":{"begin":423,"end":433},"obj":"Protein"},{"id":"T6","span":{"begin":544,"end":554},"obj":"Protein"},{"id":"T7","span":{"begin":581,"end":591},"obj":"Protein"},{"id":"T8","span":{"begin":724,"end":734},"obj":"Protein"},{"id":"T9","span":{"begin":838,"end":848},"obj":"Protein"},{"id":"T10","span":{"begin":939,"end":949},"obj":"Protein"},{"id":"T11","span":{"begin":1077,"end":1087},"obj":"Protein"},{"id":"T12","span":{"begin":1107,"end":1112},"obj":"Protein"},{"id":"T13","span":{"begin":1113,"end":1114},"obj":"Protein"},{"id":"T14","span":{"begin":1174,"end":1179},"obj":"Protein"},{"id":"T15","span":{"begin":1180,"end":1181},"obj":"Protein"},{"id":"T16","span":{"begin":1222,"end":1229},"obj":"Protein"},{"id":"T17","span":{"begin":1248,"end":1252},"obj":"Protein"},{"id":"T18","span":{"begin":1298,"end":1302},"obj":"Protein"},{"id":"T19","span":{"begin":1347,"end":1357},"obj":"Protein"},{"id":"T20","span":{"begin":1382,"end":1388},"obj":"Protein"},{"id":"T21","span":{"begin":1418,"end":1428},"obj":"Protein"},{"id":"T22","span":{"begin":1440,"end":1444},"obj":"Protein"},{"id":"T23","span":{"begin":1471,"end":1475},"obj":"Protein"},{"id":"T24","span":{"begin":1495,"end":1502},"obj":"Protein"},{"id":"T25","span":{"begin":1574,"end":1580},"obj":"Protein"},{"id":"T26","span":{"begin":1600,"end":1610},"obj":"Protein"},{"id":"T27","span":{"begin":1662,"end":1672},"obj":"Protein"},{"id":"T28","span":{"begin":1735,"end":1739},"obj":"Protein"},{"id":"T29","span":{"begin":1756,"end":1766},"obj":"Protein"},{"id":"T30","span":{"begin":1889,"end":1899},"obj":"Protein"},{"id":"T31","span":{"begin":1958,"end":1962},"obj":"Protein"}],"text":"Peroxisome proliferator-activated receptor-gamma abrogates Smad-dependent collagen stimulation by targeting the p300 transcriptional coactivator.\nLigands 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."}