JNK/AP-1 pathway is involved in tumor necrosis factor-alpha induced expression of vascular endothelial growth factor in MCF7 cells.
JNK/AP-1 pathway is involved in tumor necrosis factor-alpha induced expression of vascular endothelial growth factor in MCF7 cells.
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JNK/AP-1途径参与MCF7细胞中血管内皮生长因子的肿瘤坏死因子-Alpha诱导的表达。
DOI：
10.1016/j.biopha.2009.04.045
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发表时间：
2009-07
期刊：
影响因子：
--
通讯作者：
Han X
中科院分区：
文献类型：
--
作者：
Yin Y;Wang S;Sun Y;Matt Y;Colburn NH;Shu Y;Han X
血管内皮生长因子（VEGF）与乳腺肿瘤血管生成有关。肿瘤坏死因子-α (TNF-α)是VEGF的正调节因子。本研究旨在明确TNF-α在乳腺癌细胞系MCF7中调控VEGF表达的信号通路。通过荧光素酶报告基因检测，我们证实TNF-α显著增加MCF7细胞中激活蛋白-1 （AP-1）的转录活性。TNF-α上调AP-1家族成员c-Jun、c-Fos和JunB的表达以及c-Jun的磷酸化水平，而其他AP-1家族成员Fra-1、Fra-2和JunD不受影响。AP-1的激活与p-c-Jun-c-Jun和p-c-Jun-JunB同型二聚体的形成有关。此外，TNF-α可升高MCF7细胞中c-Jun n -末端激酶（JNK）的磷酸化水平，但不影响P38和ERK的磷酸化水平。TNF-α可显著上调VEGF mRNA和蛋白水平，而JNK抑制剂SP600125可显著逆转VEGF mRNA和蛋白水平。最后，通过染色质免疫沉淀（CHIP）实验，我们发现p-c-Jun与VEGF启动子结合并直接调节VEGF转录。这些数据表明，促炎细胞因子TNF-α是乳腺癌细胞中VEGF表达的关键调节因子，至少部分通过JNK和AP-1依赖途径。
Vascular endothelial growth factor (VEGF) has been implicated in breast tumor angiogenesis. And tumor necrosis factor-α (TNF-α) is a positive regulator of VEGF. This study was aimed to identify the signalling pathway of TNF-α in VEGF expression regulation in breast cancer cell line MCF7. Using luciferase reporter assays, we demonstrated that TNF-α significantly increased activator protein-1 (AP-1) transcriptional activity in the MCF7 cells. The expression of the AP-1 family members c-Jun, c-Fos and JunB and phosphorylation levels of c-Jun were upregulated by TNF-α, whereas other AP-1 family members Fra-1, Fra-2, and JunD were unaffected. The activation of AP-1 was associated with the formation of p-c-Jun-c-Jun and p-c-Jun-JunB homodimers. Furthermore, the phosphorylation levels of c-Jun N-terminal kinase (JNK) but not P38 and ERK were elevated by TNF-α in MCF7 cells. TNF-α potently upregulated the mRNA and protein levels of VEGF, which were significantly reversed by JNK inhibitor SP600125. Finally using chromatin immunoprecipitation (CHIP) assays, we found that p-c-Jun bound to the VEGF promoter and regulated VEGF transcription directly. These data suggest that the pro-inflammatory cytokine TNF-α is a critical regulator of VEGF expression in breast cancer cells, at least partially via a JNK and AP-1 dependent pathway.
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DOI：
10.1084/jem.172.6.1535
发表时间：
1990-12-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Clauss M;Gerlach M;Gerlach H;Brett J;Wang F;Familletti PC;Pan YC;Olander JV;Connolly DT;Stern D
通讯作者：
Stern D
影响因子：
64.8
作者：
BRENNER, DA;OHARA, M;KARIN, M
通讯作者：
KARIN, M
影响因子：
64.8
作者：
KYRIAKIS, JM;BANERJEE, P;WOODGETT, JR
通讯作者：
WOODGETT, JR
影响因子：
4.4
作者：
Hagemann, T;Wilson, J;Balkwill, FR
通讯作者：
Balkwill, FR
影响因子：
4.8
作者：
Ryuto, M;Ono, M;Kuwano, M
通讯作者：
Kuwano, M