Connective tissue growth factor gene regulation -: Requirements for its induction by transforming growth factor-β2 in fibroblasts
Connective tissue growth factor gene regulation -: Requirements for its induction by transforming growth factor-β2 in fibroblasts
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DOI：
10.1074/jbc.m210366200
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发表时间：
2003-04-11
影响因子：
4.8
通讯作者：
Abraham, DJ
中科院分区：
文献类型：
--
作者：
Leask, A;Holmes, A;Abraham, DJ
在皮肤中，促纤维化蛋白结缔组织生长因子（CTGF）不正常表达。然而，当皮肤细胞暴露于转化生长因子-β（TGF-β）时，CTGF在成纤维细胞中而不是在上皮细胞中被诱导。我们已经开始研究TGF-β对成纤维细胞选择性诱导CTGF的要求。以前我们发现这种反应是Smad依赖的。现在，我们表明，蛋白激酶C和Ras/MIEK/ERK是必要的TGF-β诱导的CTGF启动子，但不是一个通用的Smad响应启动子（SBE-lux）。CTGF启动子的诱导被c-Jun或MEKK 1拮抗，表明Ras/MEK/ ERK和JNK MAPK级联之间的适当平衡对于TGF-β诱导CTGF是必要的。我们确定了最小的CTGF启动子元件的必要性和足够的赋予TGF-β对异源启动子的反应性，并表明，一个串联重复的共识转录增强因子结合元件，5 '-GAGGAATGG-3'，是必要的这种诱导。该元件先前未显示在成纤维细胞中TGF-β诱导基因表达中发挥作用。得到移位分析表明，该序列结合的核因子是大大丰富的成纤维细胞相对于上皮细胞。因此，Smads、Ras/MEK/ERK、蛋白激酶C和与GAGGAATGG结合的成纤维细胞富集因子共同作用以驱动成纤维细胞中TGF-β介导的CTGF诱导。
In skin, the profibrotic protein connective tissue growth factor (CTGF) is not normally expressed. However, when skin cells are exposed to transforming growth factor-beta (TGF-beta), CTGF is induced in fibroblasts but not in epithelial cells. We have begun to investigate the requirements for the fibroblast-selective induction of CTGF by TGF-beta. Previously we found that this response was Smad-dependent. Now we show that protein kinase C and Ras/MIEK/ERK are necessary for the TGF-beta induction of the CTGF promoter but not of a generic Smad-responsive promoter (SBE-lux). Induction of the CTGF promoter is antagonized by c-Jun or by MEKK1, suggesting that a proper balance between the Ras/MEK/ ERK and JNK MAPK cascades is necessary for TGF-beta induction of CTGF. We identify the minimal CTGF promoter element necessary and sufficient to confer TGF-beta responsiveness to a heterologous promoter and show that a tandem repeat of a consensus transcription enhancer factor binding element, 5'-GAGGAATGG-3', is necessary for this induction. This element has not been previously shown to play a role in TGF-beta induction of gene expression in fibroblasts. Get shift analysis shows that this sequence binds nuclear factors that are greatly enriched in fibroblasts relative to epithelial cells. Thus Smads, Ras/MEK/ERK, protein kinase C, and fibroblast-enriched factors that bind GAGGAATGG act together to drive the TGF-beta-mediated induction of CTGF in fibroblasts.