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 downregulation is prominent in fibrosis and mediated, via previously unknown SMAD-signaling mechanisms. Here we show that TGF-β induces association of SMAD3 with both SMAD4, needed for translocation of the complex into the nucleus, and the essential context-sensitive corepressors E2F4 and p107. The complex mediates TGF-β-induced repression by binding to regulatory elements in the target promoter. In the PPARG promoter, 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 partial repression of PPARG transcription, 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 repressing PPARG transcription, the first finding of such dual activity within the same cell. These findings describe in detail novel mechanisms by which TGF-β represses PPARG transcription, thereby facilitating its own pro-fibrotic activity.

Нозоспецифічні Особливості Редокс-Процесів При Гострих Респіраторних Вірусних Інфекціях І Хронічних Запальних Захворюваннях Органів Дихання

“…Возбуждение TGF-β 1 /Smad3-пути в эпителиальных клетках приводит к индукции синтеза коллагена и активации эпителиально-мезенхимального перехо-да -явления, которое в настоящее время считается ключевым в развитии фиброза легких. Учитывая, что активация PPAR-γ ингибирует проявления эф-фектов TGF-β 1 /Smad3-сигнального пути, считают, что агонисты PPAR-γ могут быть использованы при лечении процессов, сопровождающихся развитием фиброза легкого [8,22,26,37,39].…”

The Myofibroblast: TGFβ-1, A Conductor which Plays a Key Role in Fibrosis by Regulating the Balance between PPARγ and the Canonical WNT Pathway

“…Human fibroblasts treated with PPARγ agonists blocked TGF-β signaling. Knockdown of either SMAD3 or SMAD4 suppresses the effects of TGF-β on PPARγ mRNA and protein expression [7]. The discovery of new drugs to control the rate of the fibro-proliferative phase is of major clinical interest.…”

“…Crosstalk between PPARγ, the canonical WNT and TGF-β1 (Figures 1 and 2) The link between TGF-β1, canonical WNT/β-catenin and PPARγ has been established [6,7,107]. TGF-β1 has been shown to activate the canonical WNT signaling, and to inhibit PPARγ.…”

“…TGF-β1 upregulation promotes the fibroblast-myofibroblast transdifferentiation and negatively regulates the expression of PPARγ. TGF-β1 inhibits PPARγ expression [7] in both fibroblasts [100] and hepatic stellate cells [121]. Conversely, PPARγ agonists directly disrupt the TGF-β1 signaling and synthesis [6,122].…”

“…Then, either the PPARγ expression is upregulated while the WNT/β-catenin pathway is downregulated, or vice versa. Myofibroblast differentiation is regulated by TGF-β1, that stimulates canonical WNT signaling and represses PPARγ [6,7]. Fibroblasts and myofibroblasts are key effectors involved in the development of fibrosis through an excessive deposition of collagen and inappropriate extracellular matrix (ECM).…”