STAT1 gene expression is enhanced by nuclear EGFR and HER2 via cooperation with STAT3.
STAT1 gene expression is enhanced by nuclear EGFR and HER2 via cooperation with STAT3.
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核EGFR和HER2通过与STAT3的配合增强STAT1基因表达。
DOI：
10.1002/mc.21936
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发表时间：
2013-12
影响因子：
4.6
通讯作者：
Lo, Hui-Wen
中科院分区：
文献类型：
--
作者：
Han, Woody;Carpenter, Richard L.;Cao, Xinyu;Lo, Hui-Wen
EGFR和HER 2都是肿瘤发生和肿瘤进展的重要介质。尽管它们作为质膜结合受体的最佳特征作用，但这两种受体都经历核转位，尽管该过程的影响仍不清楚。在这项研究中，我们提供的证据表明，EGFR上调信号转导和转录激活因子1（STAT 1），一个转录因子响应炎症信号的表达，并调节参与炎症反应的基因。EGFR对STAT 1表达的调节主要归因于EGFR的核活性。致癌转录因子STAT 3与STAT 1启动子结合，并与细胞核EGFR协同作用，显著增强STAT 1基因表达。人STAT 1基因启动子的结构表征表明启动子中存在四个功能性STAT 3结合位点及其在EGFR和STAT 3共同调控STAT 1中的重要性。组成型激活的EGFR变体EGFRvIII也与STAT 3合作，通过启动子内鉴定的STAT 3结合位点激活STAT 1基因启动子。使用人乳腺癌细胞系，我们进一步发现STAT 1，EGFR和p-STAT 3水平之间呈正相关。乳腺癌细胞中的STAT 1表达通过HER 2和heregulin刺激而转录上调，并且该水平通过活化的STAT 3进一步增强。总之，我们在这项研究中报告说，STAT 1的表达上调细胞核EGFR，EGFRvIII和HER 2和STAT 3与三种受体协同作用，以进一步增强STAT 1的表达。这些新的发现建立了促有丝分裂ErbB信号通路和STAT 1介导的炎症通路之间的新联系。
Both EGFR and HER2 are important mediators of tumorigenesis and tumor progression. Despite their best characterized roles as plasma membrane-bound receptors, both receptors undergo nuclear translocation though the impact of this process remains unclear. In this study, we provide evidence showing that EGFR upregulates expression of signal transducer and activator of transcription 1 (STAT1), a transcription factor responding to inflammatory signals and regulates genes involved in inflammatory response. EGFR regulation of STAT1 expression is primarily attributed to the nuclear activity of EGFR. The oncogenic transcription factor STAT3 binds to the STAT1 promoter and synergizes with nuclear EGFR to significantly enhance STAT1 gene expression. Structural characterization of the human STAT1 gene promoter indicates the presence of four functional STAT3-bindings sites in the promoter and their importance in STAT1 co-regulation by EGFR and STAT3. The constitutively activated EGFR variant, EGFRvIII, also cooperates with STAT3 to activate the STAT1 gene promoter through the identified STAT3-bindings sites within the promoter. Using human breast cancer cell lines, we further found a positive association between levels of STAT1, EGFR and p-STAT3. STAT1 expression is transcriptionally upregulated by HER2 and heregulin stimulation in breast cancer cells, and the level is further augmented by activated STAT3. In summary, we report in this study that STAT1 expression is upregulated by nuclear EGFR, EGFRvIII and HER2 and that STAT3 synergizes with the three receptors to further enhance STAT1 expression. These novel findings establish a novel link between the mitogenic ErbB signaling pathway and the inflammatory pathway mediated by STAT1.
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影响因子：
2.8
作者：
Dhir, R;Ni, ZY;Gao, AC
通讯作者：
Gao, AC
核表皮生长因子受体 (EGFR) 与信号转导子和转录激活子 5 (STAT5) 相互作用，激活 Aurora-A 基因表达。
影响因子：
14.9
作者：
Hung, Liang-Yi;Tseng, Joseph T.;Lee, Yi-Chao;Xia, Weiya;Wang, Ying-Nai;Wu, Min-Li;Chuang, Yu-Hsuan;Lai, Chein-Hsien;Chang, Wen-Chang
通讯作者：
Chang, Wen-Chang
影响因子：
11.5
作者：
Edwards, J;Traynor, P;Bartlett, JMS
通讯作者：
Bartlett, JMS
影响因子：
5.3
作者：
Giri, DK;Ali-Seyed, M;Hung, MC
通讯作者：
Hung, MC
影响因子：
6.1
作者：
Hamilton, LM;Torres-Lozano, C;Davies, DE
通讯作者：
Davies, DE