scholarly journals Disruption of transforming growth factor ? signaling and profibrotic responses in normal skin fibroblasts by peroxisome proliferator-activated receptor ?

2004 ◽  
Vol 50 (4) ◽  
pp. 1305-1318 ◽  
Author(s):  
Asish K. Ghosh ◽  
Swati Bhattacharyya ◽  
Gabriella Lakos ◽  
Shu-Jen Chen ◽  
Yasuji Mori ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Normal Skin ◽  
Skin Fibroblasts ◽  
Peroxisome Proliferator ◽  
Growth Factor Signaling ◽  
Peroxisome Proliferator Activated Receptor

scholarly journals Transforming growth factor β suppresses peroxisome proliferator-activated receptor γ expression via both SMAD binding and novel TGF-β inhibitory elements

2017 ◽  
Vol 474 (9) ◽  
pp. 1531-1546 ◽  
Author(s):  
Sowmya P. Lakshmi ◽  
Aravind T. Reddy ◽  
Raju C. Reddy
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Regulatory Elements ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Context Sensitive ◽  
Signaling Mechanisms ◽  
Target Promoter

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 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 the 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.

Sign in / Sign up

Export Citation Format

Share Document