AP-1 transcription factor mediates VEGF-induced endothelial cell migration and proliferation.
AP-1 transcription factor mediates VEGF-induced endothelial cell migration and proliferation.
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DOI：
10.1016/j.mvr.2016.02.004
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发表时间：
2016-05
影响因子：
3.1
通讯作者：
Zhao D
中科院分区：
文献类型：
--
作者：
Jia J;Ye T;Cui P;Hua Q;Zeng H;Zhao D
血管内皮生长因子与其内皮细胞特异性受体血管内皮生长因子受体1和血管内皮生长因子R2结合后，可诱导内皮细胞迁移、增殖和血管生成。然而，这些作用的分子机制仍不清楚。本研究探讨了血管内皮细胞生长因子是否通过激活蛋白-1转录因子家族促进人脐静脉内皮细胞的迁移和增殖。我们首次发现，在不同的条件下(PBS、DMSO或对照组)，VEGF诱导即刻早期基因AP-1家族基因的表达与JunB的深刻诱导(包括mRNA和蛋白)不同。AP-1mRNA表达的增加主要发生在转录水平。表达强效显性c-Fos(AFOS)的腺病毒抑制AP-1DNA结合活性可显著抑制血管内皮生长因子诱导的HUVEC的迁移、增殖和细胞周期蛋白D1的表达。用携带JunB shRNA的腺病毒基因敲除JunB可减少血管内皮生长因子诱导的JunB的表达，并抑制HUVEC的迁移。而表达shJunB的病毒对血管内皮细胞生长因子诱导的细胞周期蛋白D1的表达和增殖无明显影响。这些结果表明，血管内皮生长因子诱导的内皮细胞迁移主要是通过诱导JunB介导的，而促进内皮细胞增殖则是由JunB非依赖性的AP-1家族成员介导的。
VEGF, upon binding to its endothelial cell specific receptors VEGF-R1 and VEGF-R2, can induce endothelial cell migration, proliferation and angiogenesis. However, the molecular mechanism of these effects still remains unclear. In this study, we investigated whether VEGF promotes human umbilical vascular endothelial cell (HUVEC) migration and proliferation through activator protein-1 transcription factor (AP-1) family. We first showed that VEGF induces immediate-early genes AP-1 family gene expression differentially with the profound induction of JunB (both mRNA and protein) under various conditions (PBS, DMSO or control adenoviruses). The increase in AP-1 mRNA expression occurs primarily at the transcriptional level. Inhibition of AP-1 DNA binding activity by adenovirus expressing a potent dominant negative form of c-Fos (Afos) significantly attenuated VEGF-induced HUVEC migration and proliferation and cyclin D1 expression. Knockdown of JunB with adenovirus expressing JunB shRNA reduces VEGF-induced JunB expression and attenuated HUVEC migration. However the shJunB-expressing virus has no effect on VEGF-induced cyclin D1 protein expression and proliferation. These results suggest that VEGF-induced endothelial migration is mediated primarily by induction of JunB whereas the promotion of endothelial proliferation by VEGF is mediated by JunB-independent AP-1 family members.