Effects of p-CREB-1 on Transforming Growth Factor-β3 Auto-Regulation in Hepatic Stellate Cells
Effects of p-CREB-1 on Transforming Growth Factor-β3 Auto-Regulation in Hepatic Stellate Cells
复制标题
DOI：
10.1002/jcb.23017
复制
发表时间：
2011-04-01
影响因子：
4
通讯作者：
Xu, Ke Shu
中科院分区：
文献类型：
--
作者：
Deng, Liang;Li, Ying;Xu, Ke Shu
以往的研究表明，转化生长因子-β 3（TGF-β 3）在体内和体外保护肝脏免受纤维化，但其调控知之甚少。此外，TGF-β 3启动子中的cAMP反应元件（CRE）被认为是TGF-β 3自身调节的重要调节位点。因此，我们假设转录因子CREB-1（CREB-1）调节肝星状细胞（HSC）中TGF-β 3的自诱导。我们用外源性TGF-β 3激活HSC中TGF-β 3自身调节的信号通路，结果表明外源性TGF-β 3可上调TGF-β 3的蛋白和mRNA表达，并可引起CREB-1在Ser-133上的磷酸化，同时还可诱导p-CREB-1的DNA结合活性，激活TGF-β 3启动子。另外，我们分别用pGenesil-1.1-shRNA-CREB-1和pRSV-CREB-1表达载体沉默和上调CREB-1基因的表达，结果表明抑制CREB-1可以抑制外源性TGF-β 3对HSC TGF-β 3 mRNA和蛋白表达的刺激，而CREB-1的上调则可以诱导这种刺激。我们的结果表明外源性TGF-β 3通过激活CREB-1上调TGF-β 3启动子的活性，进而诱导TGF-β 3的mRNA和蛋白表达。特别是，p-CREB-1是介导TGF-β 3自身诱导的关键转录因子。J.细胞。112：1046-1054，2011. (C)2011 Wiley-Liss，Inc.
Previous studies have demonstrated that transforming growth factor-beta 3 (TGF-beta 3) protected liver against fibrosis in vivo and vitro, but its regulation is poorly understood. In addition, the cAMP-responsive element (CRE) in TGF-beta 3 promoter is recognized as an important regulatory site for TGF-beta 3 auto-regulation. Thus, we hypothesize that transcription factor CRE-binding protein-1 (CREB-1) regulates the auto-induction of TGF-beta 3 in hepatic stellate cells (HSCs). We used exogenous TGF-beta 3 to activate the signal pathway of TGF-beta 3 autoregulation in HSCs, results indicated that exogenous TGF-beta 3 could up-regulate the protein and mRNA expressions of TGF-beta 3, and provoke the phosphorylation of CREB-1 on Ser-133, besides, it could induce the DNA binding activity of p-CREB-1 and activate TGF-beta 3 promoter as well. Additionally, we used pGenesil-1.1-shRNA-CREB-1 and pRSV-CREB-1 expression vector to silence and up-regulate CREB-1 gene expression respectively, and the results indicated that inhibition of CREB-1 suppressed exogenous TGF-beta 3 stimulation of TGF-beta 3 mRNA and protein expressions in HSCs, whereas up-regulation of CREB-1 induced this stimulation. Our results indicate that exogenous TGF-beta 3 up-regulates the activity of TGF-beta 3 promoter by activating CREB-1, then induces the mRNA and protein expressions of TGF-beta 3. Especially, p-CREB-1 is a critical transcription factor in mediating TGF-beta 3 auto-induction. J. Cell. Biochem. 112: 1046-1054, 2011. (C) 2011 Wiley-Liss, Inc.