YAP/TAZ regulates TGF-β/Smad3 signaling by induction of Smad7 via AP-1 in human skin dermal fibroblasts.
YAP/TAZ regulates TGF-β/Smad3 signaling by induction of Smad7 via AP-1 in human skin dermal fibroblasts.
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DOI：
10.1186/s12964-018-0232-3
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发表时间：
2018-04-25
期刊：
影响因子：
--
通讯作者：
Quan T
中科院分区：
文献类型：
--
作者：
Qin Z;Xia W;Fisher GJ;Voorhees JJ;Quan T
转录因子雅普和TAZ作为Hippo途径的主要介质发挥作用。然而，雅普和TAZ与其他信号通路的串扰仍然相对未被探索。我们已经探索了雅普和TAZ水平对人皮肤真皮成纤维细胞中TGF-β/Smad信号通路的影响。真皮成纤维细胞中的雅普和TAZ水平在真皮成纤维细胞中通过siRNA介导的敲低而降低。通过实时定量PCR、Western分析和免疫染色检测减少雅普和TAZ对TGF-β/Smad信号传导的影响。荧光素酶报告基因分析和电泳迁移率变动分析进行了调查的转录因子的DNA结合和转录活性。同时敲除雅普和TAZ（雅普/TAZ），而不是单独敲除，会损害TGF-β1诱导的Smad 3磷酸化和Smad 3转录活性，从而抑制TGF-β靶基因的表达。这种通过降低雅普/TAZ水平的降低是由抑制性Smad 7的诱导引起的，所述抑制性Smad 7抑制TGF-β1引起的Smad 3磷酸化和活性。相反，阻止Smad 7诱导恢复了雅普/TAZ降低的成纤维细胞中Smad 3磷酸化和Smad 3转录活性。与这些发现一致，抑制雅普/TAZ转录活性，类似于降低雅普/TAZ水平，也显著诱导Smad 7和损害TGF-β/Smad信号传导。进一步的研究表明，降低雅普/TAZ的水平导致激活蛋白-1（AP-1）活性的诱导，激活的AP-1结合到Smad 7基因启动子中的DNA序列，并且这些AP-1结合序列的缺失实质上降低了Smad 7启动子报告基因活性。在人皮肤成纤维细胞中，雅普/TAZ与转录因子AP-1和Smad 7协同作用以调节TGF-β信号传导。雅普/TAZ水平的降低导致AP-1活性的激活，其诱导Smad 7。Smad 7抑制TGF-β通路。本文的在线版本（10.1186/s12964-018-0232-3）包含补充材料，可供授权用户使用。
Transcription factors YAP and TAZ function as the primary mediators of the Hippo pathway. Yet, crosstalk of YAP and TAZ with other signaling pathways remains relatively unexplored. We have explored the impact of YAP and TAZ levels on the TGF-β/Smad signaling pathway in human skin dermal fibroblasts. YAP and TAZ levels in dermal fibroblasts were reduced in dermal fibroblasts by siRNA-mediated knockdown. The effects of YAP and TAZ reduction on TGF-β/Smad signaling were examined by quantitative real-time PCR, Western analysis, and immunostaining. Luciferase reporter assays and electrophoretic mobility shift assays were conducted to investigate the transcription factor DNA-binding and transcriptional activities. Knockdown of both YAP and TAZ (YAP/TAZ), but not either separately, impaired TGF-β1-induced Smad3 phosphorylation and Smad3 transcriptional activity, thereby inhibiting the expression of TGF-β target genes. This reduction by reduced levels of YAP/TAZ results from induction of inhibitory Smad7, which inhibits Smad3 phosphorylation and activity by TGF-β1. Conversely, prevention of Smad7 induction restores Smad3 phosphorylation and Smad3 transcriptional activity in fibroblasts that have reduced YAP/TAZ. In agreement with these findings, inhibition of YAP/TAZ transcriptional activity, similar to the reduction of YAP/TAZ levels, also significantly induced Smad7 and impaired TGF-β/Smad signaling. Further investigations revealed that reduced levels of YAP/TAZ led to induction of activator protein-1 (AP-1) activity, Activated AP-1 bound to DNA sequences in the Smad7 gene promoter, and deletion of these AP-1 binding sequences substantially reduced Smad7 promoter reporter activity. YAP/TAZ functions in concert with transcription factor AP-1 and Smad7 to regulate TGF-β signaling, in human dermal fibroblasts. Reduction of YAP/TAZ levels leads to activation of AP-1 activity, which induces Smad7. Smad7 suppresses the TGF-β pathway. The online version of this article (10.1186/s12964-018-0232-3) contains supplementary material, which is available to authorized users.
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影响因子：
4.8
作者：
Hiemer, Samantha E.;Szymaniak, Aleksander D.;Varelas, Xaralabos
通讯作者：
Varelas, Xaralabos
影响因子：
4.8
作者：
Leask, A;Holmes, A;Abraham, DJ
通讯作者：
Abraham, DJ
DOI：
10.1073/pnas.062010399
发表时间：
2002-03-19
影响因子：
11.1
作者：
Dong, CM;Zhu, SK;Goldschmidt-Clermont, PJ
通讯作者：
Goldschmidt-Clermont, PJ
DOI：
10.1016/j.molbrainres.2003.11.008
发表时间：
2004-02-05
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Chattopadhyay, N;Tfelt-Hansen, J;Brown, EM
通讯作者：
Brown, EM
从受体到 Smads 的 TGF-β 信号传导
影响因子：
7.2
作者：
Hata A;Chen YG
通讯作者：
Chen YG