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.
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Cover Image
Cover Image
3D reconstructions of 4 individual Escherichia coli cells that have been serially sectioned and immunolabelled to unambiguously identify a membrane protein of interest (TatA, position marked by spheres). The reconstructions illustrate a linear clustering of TatA protein in the inner membrane of E. coli – a previously uncharacterised distribution for this protein. For more information, please see article by Sarah M. Smith et al, pages 1495–1508. Image provided by Sarah M. Smith.
Transforming growth factor β suppresses peroxisome proliferator-activated receptor γ expression via both SMAD binding and novel TGF-β inhibitory elements
Sowmya P. Lakshmi, Aravind T. Reddy, Raju C. Reddy; Transforming growth factor β suppresses peroxisome proliferator-activated receptor γ expression via both SMAD binding and novel TGF-β inhibitory elements. Biochem J 1 May 2017; 474 (9): 1531–1546. doi: https://doi.org/10.1042/BCJ20160943
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