TNFα-induced ATF3 expression is bidirectionally regulated by the JNK and ERK pathways in vascular endothelial cells
TNFα-induced ATF3 expression is bidirectionally regulated by the JNK and ERK pathways in vascular endothelial cells
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DOI：
10.1111/j.1356-9597.2004.00707.x
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发表时间：
2004-01-01
期刊：
影响因子：
2.1
通讯作者：
Hagiwara, M
中科院分区：
文献类型：
--
作者：
Inoue, K;Zama, T;Hagiwara, M
ATF 3（Activating transcription factor 3）是CREB/ATF家族的成员之一，在哺乳动物细胞中可被应激和生长因子诱导，在心血管系统中发挥重要作用。然而，除了JNK通路参与外，目前对ATF 3的诱导是如何调节的知之甚少。在这里，我们研究了MAPK通路参与TNF α（肿瘤坏死因子α）诱导的血管内皮细胞中ATF 3表达的不同作用。在人脐静脉内皮细胞中，组成型活性MKK 7（MAPK激酶7）的表达增加了ATF 3阳性细胞的数量，显性阴性MKK 7抑制TNF α诱导的ATF 3表达，表明需要JNK途径。相反，组成型活性或显性负性MEK 1/2（MAPK/ERK激酶1/2）的表达分别抑制或增强TNF α介导的ATF 3诱导。为了支持这一点，MEK 1/2特异性抑制剂U 0126增强了TNF α诱导的ATF 3的表达。此外，ERK途径抑制TNF α介导的ATF 3 mRNA的诱导，但不抑制其稳定性，表明ERK活性参与ATF 3基因的转录调控。我们的研究结果表明，TNF α诱导的ATF 3基因表达是双向调节的JNK和ERK途径在血管内皮细胞。
ATF3 (Activating transcription factor 3), a member of the CREB/ATF family, can be induced by stress and growth factors in mammalian cells, and is thought to play an important role in the cardiovascular system. However, little is currently known about how the induction of ATF3 is regulated, except that the JNK pathway is involved. Here, we investigated the differential roles of the MAPK pathways involved in TNFalpha (tumour necrosis factor alpha)-induced ATF3 expression in vascular endothelial cells. In human umbilical vein endothelial cells, the expression of constitutively active MKK7 (MAPK kinase 7) increased the number of ATF3-positive cells, and dominant negative MKK7 suppressed the TNFalpha-induced expression of ATF3, indicating a requirement for the JNK pathway. In contrast, the expression of constitutively active or dominant negative MEK1/2 (MAPK/ERK kinase 1/2) suppressed or enhanced TNFalpha-mediated induction of ATF3, respectively. In support of this, the MEK1/2 specific inhibitor U0126 enhanced the expression of ATF3 induced by TNFalpha. Furthermore, the ERK pathway inhibits the TNFalpha-mediated induction of ATF3 mRNA, but not its stability, suggesting the involvement of ERK activity in the transcriptional regulation of the ATF3 gene. Our results suggest that TNFalpha-induced ATF3 gene expression is bidirectionally regulated by the JNK and ERK pathways in vascular endothelial cells.