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TNFα‐induced ATF3 expression is bidirectionally regulated by the JNK and ERK pathways in vascular endothelial cells
Author(s) -
Inoue Koichi,
Zama Takeru,
Kamimoto Takahiro,
Aoki Ryoko,
Ikeda Yasuo,
Kimura Hiroshi,
Hagiwara Masatoshi
Publication year - 2004
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1356-9597.2004.00707.x
Subject(s) - mapk/erk pathway , atf3 , activating transcription factor , biology , tumor necrosis factor alpha , microbiology and biotechnology , umbilical vein , protein kinase a , signal transduction , creb , kinase , transcription factor , cancer research , gene expression , immunology , unfolded protein response , gene , promoter , genetics , in vitro , endoplasmic reticulum
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 TNFα (tumour necrosis factor α)‐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 TNFα‐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 TNFα‐mediated induction of ATF3, respectively. In support of this, the MEK1/2 specific inhibitor U0126 enhanced the expression of ATF3 induced by TNFα. Furthermore, the ERK pathway inhibits the TNFα‐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 TNFα‐induced ATF3 gene expression is bidirectionally regulated by the JNK and ERK pathways in vascular endothelial cells.