Suppression of HGF receptor gene expression by oxidative stress is mediated through the interplay between Sp1 and Egr-1.
Suppression of HGF receptor gene expression by oxidative stress is mediated through the interplay between Sp1 and Egr-1.
复制标题
氧化应激对 HGF 受体基因表达的抑制是通过 Sp1 和 Egr-1 之间的相互作用介导的。
DOI：
10.1152/ajprenal.00426.2002
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Liu,Youhua
中科院分区：
文献类型：
--
作者：
Zhang,Xianghong;Liu,Youhua
肝细胞生长因子（HGF）受体是原癌基因的产物，受多种细胞因子和细胞外环境因子的调控。在这份报告中，我们表明，c-met表达显着抑制氧化应激。用0.5 mM H2 O2处理小鼠肾内髓集合管上皮细胞可抑制c-met mRNA和蛋白的表达，并伴有Egr-1转录因子的诱导。Egr-1在肾上皮细胞中的异位表达以剂量依赖性方式显著抑制内源性c-met表达，表明Egr-1在介导c-met抑制中的致病作用。H2 O2诱导c-met抑制的顺式作用元件位于c-met启动子的-223到-68位核苷酸，其中存在一个不完全的Egr-1和三个Sp1结合位点。Egr-1显著抑制c-met启动子活性，但不直接与c-met基因中的剪切作用元件结合。氧化应激对Egr-1的诱导减弱了Sp1与其同源位点的结合，但不影响肾上皮细胞中Sp1的丰度。免疫沉淀发现Egr-1与Sp1通过形成Sp1/Egr-1复合物而发生物理相互作用，这可能导致未结合的Sp1作为该基因的转录激活因子的可用性降低。因此，它似乎是由氧化应激的c-met表达的抑制介导的Sp1和Egr-1转录因子之间的相互作用。我们的研究结果揭示了一种新的转录调控机制，Egr-1螯合Sp1作为转录激活c-metvia物理相互作用。
Hepatocyte growth factor (HGF) receptor, the product of thec-metprotooncogene, is transcriptionally regulated by a wide variety of cytokines as well as extracellular environmental cues. In this report, we demonstrate that c-met expression was significantly suppressed by oxidative stress. Treatment of mouse renal inner medullary collecting duct epithelial cells with 0.5 mM H2O2inhibited c-met mRNA and protein expression, which was concomitant with induction of Egr-1 transcription factor. Ectopic expression of Egr-1 in renal epithelial cells markedly inhibited endogenous c-met expression in a dose-dependent fashion, suggesting a causative effect of Egr-1 in mediating c-met suppression. Thecis-acting element responsible for H2O2-induced c-met inhibition was localized at nucleotide position −223 to −68 of c-met promoter, in which reside an imperfect Egr-1 and three Sp1-binding sites. Egr-1 markedly suppressed c-met promoter activity but did not directly bind to itscis-acting element in thec-metgene. Induction of Egr-1 by oxidative stress attenuated the binding of Sp1 to its cognate sites, but it did not affect Sp1 abundance in renal epithelial cells. Immunoprecipitation uncovered that Egr-1 physically interacted with Sp1 by forming the Sp1/Egr-1 complex, which presumably resulted in a decreased availability of unbound Sp1 as a transcriptional activator for thec-metgene. Thus it appears that inhibition of c-met expression by oxidative stress is mediated by the interplay between Sp1 and Egr-1 transcription factors. Our findings reveal a novel transcriptional regulatory mechanism by which Egr-1 sequesters Sp1 as a transcriptional activator ofc-metvia physical interaction.