Basic fibroblast growth factor antagonizes transforming growth factor-β1-induced smooth muscle gene expression through extracellular signal-regulated kinase 1/2 signaling pathway activation
Basic fibroblast growth factor antagonizes transforming growth factor-β1-induced smooth muscle gene expression through extracellular signal-regulated kinase 1/2 signaling pathway activation
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DOI：
10.1161/01.atv.0000136548.17816.07
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发表时间：
2004-08-01
影响因子：
8.7
通讯作者：
Kurabayashi, M
中科院分区：
文献类型：
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作者：
Kawai-Kowase, K;Sato, H;Kurabayashi, M
目的-转化生长因子-β1 (TGFbeta1) 和成纤维细胞生长因子 (FGF) 家族在血管发育和血管疾病的发病机制中发挥着关键作用。然而，这些生长因子引起的细胞内信号传导的相互作用尚不清楚。本研究旨在研究介导TGFbeta1和碱性FGF（bFGF）对平滑肌细胞（SMC）基因表达影响的分子机制。方法和结果-在多能10T1/2细胞中检查TGFbeta1诱导SMC基因表达，包括平滑肌蛋白22-α（SM22α）和平滑肌α-肌动蛋白。 c-Src-酪氨酸激酶抑制剂和蛋白质合成抑制剂放线菌酮可抑制 TGFbeta1 引起的这些 mRNA 水平的显着增加。对 SM22α 启动子进行删除和定点突变分析的功能研究表明，TGFbeta1 通过 CC(A/T-rich)(6)GG (CArG) 盒激活 SM22α 启动子，该盒充当血清反应因子 (SRF) 结合位点。 TGFbeta1 通过增加 SRF 基因的转录来增加 SRF 表达。在 bFGF 存在的情况下，TGFbeta1 对 SMC 标记基因表达的诱导作用显着减弱。瞬时转染测定表明，bFGF 显着抑制 TGFbeta1 对 SM22α 启动子驱动的荧光素酶活性的诱导，而 bFGF 对 TGFbeta1 介导的 SRF 表达和 SRF:DNA 结合活性的增加没有影响。丝裂原激活蛋白激酶激酶-1 (MEK1) 抑制剂 PD98059 消除了 bFGF 介导的对 TGFbeta1 诱导的 SMC 基因表达的抑制。结论 - 我们的数据表明，bFGF 诱导的 MEK/细胞外信号调节激酶信号传导通过抑制 SRF 功能在 TGFbeta1 诱导的 SMC 基因表达中发挥拮抗作用。这些数据表明 bFGF 和 TGFbeta1 对 SMC 基因表达的相反作用控制着 SMC 的表型可塑性。
Objective-Transforming growth factor-beta1 (TGFbeta1) 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 TGFbeta1 and basic FGF (bFGF) on smooth muscle cell (SMC) gene expression.Methods and Results-TGFbeta1 induction of SMC gene expression, including smooth muscle protein 22-alpha (SM22alpha) and smooth muscle alpha-actin, was examined in the pluripotent 10T1/2 cells. Marked increase in these mRNA levels by TGFbeta1 was inhibited by c-Src-tyrosine kinase inhibitors and protein synthesis inhibitor cycloheximide. Functional studies with deletion and site-directed mutation analysis of the SM22alpha promoter demonstrated that TGFbeta1 activated the SM22alpha promoter through a CC(A/T-rich)(6)GG (CArG) box, which serves as a serum response factor (SRF)-binding site. TGFbeta1 increased SRF expression through an increase in transcription of the SRF gene. In the presence of bFGF, TGFbeta1 induction of SMC marker gene expression was significantly attenuated. Transient transfection assays showed that bFGF significantly suppressed induction of the SM22alpha promoter-driven luciferase activity by TGFbeta1, whereas bFGF had no effects on the TGFbeta1-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 TGFbeta1-induced SMC gene expression.Conclusion-Our data suggest that bFGF-induced MEK/extracellular signal-regulated kinase signaling plays an antagonistic role in TGFbeta1-induced SMC gene expression through suppression of the SRF function. These data indicate that opposing effects of bFGF and TGFbeta1 on SMC gene expression control the phenotypic plasticity of SMCs.