Gene expression of the lysophosphatidic acid receptor 1 is a target of transforming growth factor beta.
Gene expression of the lysophosphatidic acid receptor 1 is a target of transforming growth factor beta.
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DOI：
10.1038/onc.2012.325
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发表时间：
2013-06-27
期刊：
影响因子：
8
通讯作者：
Fang, X.
中科院分区：
文献类型：
--
作者：
Wu, J.;Mukherjee, A.;Lebman, D. A.;Fang, X.
溶血磷脂酸（LPA）受体LPA 1/Edg 2是第一个被鉴定的LPA受体。虽然LPA 1广泛的组织分布和生物学功能已被充分研究，但对LPA 1的转录调控知之甚少。在目前的研究中，我们发现LPA 1是转化生长因子β（TGFβ）介导的抑制的生理靶点。在正常和肿瘤细胞中，TGFβ抑制LPA 1启动子活性、LPA 1 mRNA表达、LPA 1依赖性趋化性和肿瘤细胞侵袭。用慢病毒转导的shRNA敲低TGFβ细胞内效应物Smad 3或Smad 4减轻了TGFβ的这些抑制作用。有趣的是，LPA 1启动子含有两个潜在的TGFβ抑制元件（TIE），每个TIE由一个Smad结合位点和一个相邻的E2 F4/5元件组成，在结构上类似于在明确定义的TGFβ靶基因c-myc的启动子上发现的TIE。缺失和点突变分析表明，位于转录起始位点401 bp处的远端TIE是TGFβ抑制LPA 1启动子所必需的。DNA下拉测定显示，-401 TIE能够结合TGFβ处理的细胞中的Samd 3和E2 F4。TGFβ诱导的Smad复合物与LPA 1基因启动子的天然-401 TIE序列的结合通过染色质免疫沉淀测定进一步验证。因此，我们确定了TGFβ在控制LPA 1表达和LPA 1偶联生物学功能中的新作用，将LPA 1添加到TGFβ抑制的靶基因列表中。
The lysophosphatidic acid (LPA) receptor LPA1/Edg2 is the first identified LPA receptor. Although its wide tissue distribution and biological functions have been well studied, little is known about how LPA1 is transcriptionally regulated. In the current study, we showed that LPA1 is a physiological target of transforming growth factor beta (TGFβ)-mediated repression. In both normal and neoplastic cells, TGFβ inhibits LPA1 promoter activity, LPA1 mRNA expression, and LPA1-dependent chemotaxis and tumor cell invasion. Knockdown of the TGFβ intracellular effector Smad3 or Smad4 with lentivirally transduced shRNA relieved these inhibitory effects of TGFβ. Interestingly, the LPA1 promoter contains two potential TGFβ inhibitory elements (TIEs), each consisting of a Smad binding site and an adjacent E2F4/5 element, structurally similar to the TIE found on the promoter of the well-defined TGFβ target gene c-myc. Deletion and point mutation analyses indicate that the distal TIE located at 401 bp from the transcription initiation site, is required for TGFβ repression of the LPA1 promoter. A DNA pull-down assay showed that the -401 TIE was capable of binding Samd3 and E2F4 in TGFβ-treated cells. TGFβ-induced binding of the Smad complex to the native -401 TIE sequence of the LPA1 gene promoter was further verified by chromatin immunoprecipitation assays. We therefore identified a novel role of TGFβ in the control of LPA1 expression and LPA1-coupled biological functions, adding LPA1 to the list of TGFβ-repressed target genes.
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影响因子：
29.4
作者：
Lin S;Wang D;Iyer S;Ghaleb AM;Shim H;Yang VW;Chun J;Yun CC
通讯作者：
Yun CC
影响因子：
8.4
作者：
Marshall, Jean-Claude;Collins, Joshua;Marino, Natascia;Steeg, Patricia
通讯作者：
Steeg, Patricia
影响因子：
11.2
作者：
Deckers, M;van Dinther, M;ten Dijke, P
通讯作者：
ten Dijke, P
影响因子：
8
作者：
Jazag, A;Ijichi, H;Omata, M
通讯作者：
Omata, M
DOI：
10.1073/pnas.97.24.13384
发表时间：
2000-11-21
影响因子：
11.1
作者：
Contos, JJA;Fukushima, N;Chun, J
通讯作者：
Chun, J