on June 24, 2004
Published online before print June 24, 2004, doi: 10.1161/01.ATV.0000136548.17816.07
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Submitted on December 26, 2003
Accepted on May 24, 2004
Basic Fibroblast Growth Factor Antagonizes Transforming Growth Factor-
1-Induced Smooth Muscle Gene Expression Through Extracellular Signal-Regulated Kinase 1/2 Signaling Pathway Activation
Keiko Kawai-Kowase ;
From the Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Gunma, Japan.
* To whom correspondence should be addressed. E-mail: mkuraba{at}med.gunma-u.ac.jp.
Objective--Transforming growth factor-
1 (TGF1) and fibroblast growth factor (FGF) families play a pivotal role during vascular development and in the pathogenesis of vascular disease. However, the interaction of intracellular signaling evoked by each of these growth factors is not well understood. The present study was undertaken to examine the molecular mechanisms that mediate the effects of TGF1 and basic FGF (bFGF) on smooth muscle cell (SMC) gene expression.
Methods and Results--TGF1 induction of SMC gene expression, including smooth muscle protein 22-
(SM22) and smooth muscle -actin, was examined in the pluripotent 10T1/2 cells. Marked increase in these mRNA levels by TGF1 was inhibited by c-Src-tyrosine kinase inhibitors and protein synthesis inhibitor cycloheximide. Functional studies with deletion and site-directed mutation analysis of the SM22 promoter demonstrated that TGF1 activated the SM22 promoter through a CArG box, which serves as a serum response factor (SRF)-binding site. TGF1 increased SRF expression through an increase in transcription of the SRF gene. In the presence of bFGF, TGF1 induction of SMC marker gene expression was significantly attenuated. Transient transfection assays showed that bFGF significantly suppressed induction of the SM22 promoter-driven luciferase activity by TGF1, whereas bFGF had no effects on the TGF1-mediated increase in SRF expression and SRF:DNA binding activity. Mitogen-activated protein kinase kinase-1 (MEK1) inhibitor PD98059 abrogated the bFGF-mediated suppression of TGF1-induced SMC gene expression.
Conclusion--Our data suggest that bFGF-induced MEK/extracellular signal-regulated kinase signaling plays an antagonistic role in TGF1-induced SMC gene expression through suppression of the SRF function. These data indicate that opposing effects of bFGF and TGF1 on SMC gene expression control the phenotypic plasticity of SMCs.
Key words: basic fibroblast growth factor • transforming growth factor-
1 •
serum response factor •
SM22 •
smooth muscle cells
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