Transforming growth factor β suppresses peroxisome proliferator-activated receptor γ expression via both SMAD binding and novel TGF-β inhibitory elements.
Transforming growth factor β suppresses peroxisome proliferator-activated receptor γ expression via both SMAD binding and novel TGF-β inhibitory elements.
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DOI：
10.1042/bcj20160943
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发表时间：
2017-04-24
期刊：
影响因子：
--
通讯作者：
Reddy RC
中科院分区：
文献类型：
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作者：
Lakshmi SP;Reddy AT;Reddy RC
转化生长因子β(转化生长因子-β)促进伤口愈合，当调控失调时，可导致病理性纤维化。转化生长因子-β和抗纤维化核激素受体过氧化物酶体增殖物激活受体γ(PPARγ)相互抑制彼此的表达，这种PPARγ下调在纤维化中显著存在，并通过先前未知的SMAD信号机制介导。在这里，我们表明转化生长因子-β诱导Smad3与Smad4，以及必要的上下文敏感辅阻遏子E2F4和p107的结合，Smad4是复合体移位到核中所需的。该复合体通过与靶启动子中的调控元件结合来介导转化生长因子-β诱导的抑制。在PPARG启动子中，我们发现Smad3-Smad4复合体既与先前未知的共识转化生长因子-β抑制元件(TIE)结合，也与规范的Smad3结合元件(SBE)结合。此外，Tie和SBEs独立地介导了PPARG转录的部分抑制，这首次证明了Tie和SBEs在同一启动子中发挥作用。此外，转化生长因子-β处理的成纤维细胞除了抑制PPARG转录外，还含有激活SMAD靶基因的SMAD复合体，这是在同一细胞中首次发现这种双重活性。这些发现详细描述了转化生长因子-β抑制PPARG转录的新机制，从而促进其自身的促纤维化活性。
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.