© 2001 American Heart Association, Inc.
Vascular Biology |
Function of GATA Transcription Factors in Induction of Endothelial Vascular Cell Adhesion Molecule-1 by Tumor Necrosis Factor-
From the Department of Molecular Biology and Medicine (M.U., C.M., T.H., T.K.), Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan, and the Center for Tsukuba Advanced Research Alliance (N.M., M.Y.), University of Tsukuba, Tsukuba, Japan.
Correspondence to Michihisa Umetani, Department of Molecular Biology and Medicine, #35, RCAST, University of Tokyo, 4-6-1 Komaba, Meguro, Tokyo 153-0084, Japan. E-mail umetani-tky{at}umin.ac.jp
Abstract—Endothelial
vascular cell adhesion molecule-1 (VCAM-1) is expressed in response to
cytokine stimulation and plays a critical role in inflammatory
reactions. Previously, we developed a novel VCAM-1
inhibitor that acts through a mechanism independent of
nuclear factor-
B activity. It suppresses the binding activity of
GATA proteins in cytokine-stimulated
endothelial cells, which may be related to the
anti–VCAM-1 induction effect of this drug. In this study, we
investigated the role of GATA proteins in the induction of VCAM-1 by
tumor necrosis factor-
(TNF-) in human
endothelial cells. The mRNA expression of GATA-6 was
increased, whereas GATA-3 mRNA was decreased by TNF- stimulation.
Electrophoretic mobility shift assay showed that TNF- stimulation
increased the DNA binding of GATA-6 but decreased that of GATA-3.
Experiments using protein overexpression or antisense
oligonucleotides revealed that GATA-6 potently acts as
a positive regulator of VCAM-1 gene transcription. In contrast,
overexpression of GATA-3 was able to suppress TNF-–induced VCAM-1
expression. Our results provide evidence of the importance of GATA
proteins in the induction of VCAM-1 by TNF- in vascular
endothelial cells. The switch from GATA-3 to GATA-6 is
taken to be an important transcriptional control event in TNF-
induction of
VCAM-1.
Key Words: endothelial cells • vascular cell adhesion molecule-1 • GATA transcription factor • tumor necrosis factor- • human umbilical vein endothelial cells
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