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首页> 外文期刊>Journal of Cellular Physiology >Interaction of smad3 with a proximal smad-binding element of the human alpha2(I) procollagen gene promoter required for transcriptional activation by TGF-beta.
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Interaction of smad3 with a proximal smad-binding element of the human alpha2(I) procollagen gene promoter required for transcriptional activation by TGF-beta.

机译：近端smad-binding smad3互动元素的人类alpha2 (I)胶原基因所需的启动子转录激活及护。

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摘要

Transcription of the alpha2(I) collagen gene (COL1A2) in fibroblasts is potently induced by transforming growth factor-beta (TGF-beta). Smad family proteins function as intracellular signal transducers for TGF-beta that convey information from the cell membrane to the nucleus. In the present study, we establish the functional requirement for endogenous Smad3 and Smad4 in TGF-beta-stimulated COL1A2 transcription in human skin fibroblasts in vitro. Furthermore, using transfections with a series of 5' deletions of the human COL1A2 promoter, we identify a proximal region between -353 and -148 bp, which is required for full stimulation of transcription by a constitutively active TGF-beta type I receptor. This region of the COL1A2 promoter contains a CAGA motif also found in the promoter of the plasminogen activator inhibitor-1. Substitutions disrupting this sequence decreased the binding of nuclear extracts or recombinant Smad3 to the CAGACA oligonucleotide, and markedly reduced the transcriptional response to TGF-beta or overexpressed Smad3 in transient transfection assays. The insertion of tandem repeats of CAGACA conferred TGF-beta stimulation to a heterologous minimal promoter-reporter construct. Inhibition of endogenous Smad expression in fibroblasts by antisense oligonucleotides or cDNA against Smad3 or Smad4, and transfection of COL1A2 promoter constructs into Smad4-deficient breast adenocarcinoma cells, indicated the critical role of Smads for the full TGF-beta response. The importance of Smad binding to the CAGACA box of COL1A2 was further established by transcriptional decoy oligonucleotide competition. Taken together, the results identify a functional Smad-binding element of the COL1A2 promoter harboring a CAGACA consensus sequence that is both necessary and sufficient for stimulation by TGF-beta, and demonstrate that interaction of this Smad-binding element with endogenous Smads is required for the full TGF-beta response in fibroblasts. Copyright 2000 Wiley-Liss, Inc.
机译：转录的alpha2 (I)胶原蛋白基因(COL1A2)成纤维细胞是有说服力地诱导转化生长因子(及)。家族蛋白作为细胞内信号传感器及传递信息从原子核的细胞膜。目前的研究中,我们建立的功能内源性Smad3和Smad4的要求在人类TGF-beta-stimulated COL1A2转录皮肤成纤维细胞在体外。转染的一系列5 '删除人类COL1A2启动子,我们确定一个近端地区-353至-148个基点,这是需要完整的转录的刺激一个既定的活跃的I型受体。COL1A2启动子的这个区域包含一个CAGA主题还发现的启动子纤溶酶原激活物inhibitor-1。破坏这个序列的约束力下降核提取物或重组Smad3CAGACA寡核苷酸,明显减少了及或转录反应过表达Smad3瞬时转染化验。授予及不同的刺激最小promoter-reporter构造。成纤维细胞的内源性Smad表达式反义寡核苷酸、cDNA Smad3和Smad4 COL1A2启动子的转染构造成Smad4-deficient乳房腺癌的细胞,表明了至关重要的作用Smads的完整及响应。Smad绑定到CAGACA盒的重要性COL1A2进一步建立了转录诱饵寡核苷酸的竞争。在一起,结果识别功能Smad-binding COL1A2子元素窝藏CAGACA共识序列两个必要和充分的刺激及,表明相互作用这与内生Smads Smad-binding元素需要完整的鉴定及反应吗成纤维细胞。

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