title: Transforming growth factor β suppresses peroxisome proliferator-activated receptor γ expression via both SMAD binding and novel TGF-β inhibitory elements.
abstract: Transforming growth factor β (TGF-β) contributes to wound healing and, when dysregulated, to pathological fibrosis. TGF-β and the anti-fibrotic nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) repress each other's expression, and such PPARγ down-regulation is prominent in fibrosis and mediated, via previously unknown SMAD-signaling mechanisms. Here, we show that TGF-β induces the association of SMAD3 with both SMAD4, needed for translocation of the complex into the nucleus, and the essential context-sensitive co-repressors E2F4 and p107. The complex mediates TGF-β-induced repression by binding to regulatory elements in the target promoter. In thePPARGpromoter, we found that the SMAD3-SMAD4 complex binds both to a previously unknown consensus TGF-β inhibitory element (TIE) and also to canonical SMAD-binding elements (SBEs). Furthermore, the TIE and SBEs independently mediated the partial repression ofPPARGtranscription, the first demonstration of a TIE and SBEs functioning within the same promoter. Also, TGF-β-treated fibroblasts contained SMAD complexes that activated a SMAD target gene in addition to those repressingPPARGtranscription, the first finding of such dual activity within the same cell. These findings describe in detail novel mechanisms by which TGF-β repressesPPARGtranscription, thereby facilitating its own pro-fibrotic activity.
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, U.S.A.|Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, U.S.A.
authors.forename: Sowmya P
authors.initials: SP
authors.lastname: Lakshmi
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, U.S.A.|Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, U.S.A.
authors.forename: Aravind T
authors.initials: AT
authors.lastname: Reddy
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, U.S.A. reddyrc@upmc.edu.|Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, U.S.A.
authors.forename: Raju C
authors.initials: RC
authors.lastname: Reddy
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism*; D051901:Smad4 Protein / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D047495:PPAR gamma; D012333:RNA, Messenger; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051900:Smad3 Protein; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta