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Blood, 15 September 2000, Vol. 96, No. 6, pp. 2140-2148
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Homocysteine-responsive ATF3 gene expression in human vascular
endothelial cells: activation of c-Jun NH2-terminal kinase
and promoter response element
Yong Cai,
Chun Zhang,
Tigre Nawa,
Teijiro Aso,
Makiko Tanaka,
Satoru Oshiro,
Hidenori Ichijo, and
Shigetaka Kitajima
From the Department of Biochemical Genetics, Medical
Research Institute, and the Department of Biomaterials Science, Faculty
of Dentistry, Tokyo Medical and Dental University; and the Department
of Viral Oncology, Cancer Institute, Japanese Foundation for Cancer
Research, Tokyo, Japan.
Activating transcription factor (ATF) 3 is a member of ATF/cyclic
adenosine monophosphate (cAMP)-responsive element binding protein (ATF/CREB) family of transcription factors and functions as a
stress-inducible transcriptional repressor. To understand the
stress-induced gene regulation by homocysteine, we investigated activation of the ATF3 gene in human endothelial cells. Homocysteine caused a rapid induction of ATF3 at the transcriptional level. This
induction was preceded by a rapid and sustained activation of c-Jun
NH2-terminal kinase/stress-activated protein kinase
(JNK/SAPK), and dominant negative mitogen-activated protein kinase
kinase 4 and 7 abolished these effects. The effect of
homocysteine appeared to be specific, because cysteine or homocystine
had no appreciable effect, but it was mimicked by dithiothreitol and
 -mercaptoethanol as well as tunicamycin. The homocysteine effect was
not inhibited by an active oxygen scavenger. Deletion analysis of the
5' flanking sequence of the ATF3 gene promoter revealed that one of the
major elements responsible for the induction by homocysteine is an
ATF/cAMP responsive element (CRE) located at  92 to 85 relative to
the transcriptional start site. Gel shift, immunoprecipitation, and cotransfection assays demonstrated that a complex (or complexes) containing ATF2, c-Jun, and ATF3 increased binding to the ATF/CRE site
in the homocysteine-treated cells and activated the ATF3 gene
expression, while ATF3 appeared to repress its own promoter. These data
together suggested a novel pathway by which homocysteine causes the
activation of JNK/SAPK and subsequent ATF3 expression through its
reductive stress. Activation of JNK/SAPK and ATF3 expression in
response to homocysteine may have a functional role in
homocysteinemia-associated endothelial dysfunction.
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