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首页> 外文学位 >EGF downregulates tropoelastin expression in lung fibroblasts through stabilization of Smad corepressor TGIF.
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EGF downregulates tropoelastin expression in lung fibroblasts through stabilization of Smad corepressor TGIF.

机译：EGF通过稳定Smad核心抑制剂TGIF来下调肺成纤维细胞中原弹性蛋白的表达。

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摘要

Elastin, a principal component of elastic fibers, maintains the resilience and structural integrity of airways and blood vessels in the mature lung. Elastin is a remarkably durable polymer, assembled from cross-linked monomers of tropoelastin, its soluble precursor. Once deposited, elastin essentially does not turn over in healthy lung during the life span of the organism. Emphysema, however, is characterized by irreversible destruction of elastic fibers, which is the consequence of increased elastolysis and insufficient repair of elastin. The mechanism underlying the insufficient repair of elastin is still under investigation. We have previously reported that neutrophil elastase downregulates tropoelastin expression in rat lung fibroblasts through the transactivation of the epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase kinase (Mek)/extracellular signal-regulated kinases 1 and 2 (Erk) signaling pathway, which is dependent on the release of epidermal growth factor (EGF)-like growth factors. In the present study, we investigated the mechanism by which EGF downregulates tropoelastin expression. We found that tropoelastin expression in the rat fetal lung fibroblast line RFL-6 is primarily maintained by autocrine transforming growth factor-beta (TGF-beta). We demonstrated that EGF, via the EGFR/Mek/Erk pathway, downregulates tropoelastin expression through inhibition of TGF-beta signaling. We showed that EGF does not prevent the TGF-beta-induced nuclear accumulation of Smad2/3; rather, EGF stabilizes Smad corepressor TG-interacting factor (TGIF) through EGFR/Mek/Erk-mediated phosphorylation of TGIF. We confirmed that elevated TGIF levels are sufficient to inhibit TGF-beta-induced tropoelastin expression in RFL-6 cells. Moreover, elevated TGIF levels are essential for EGF to downregulate tropoelastin expression, as the EGF inhibition of tropoelastin expression is prevented in cells whose TGIF levels are knocked down by RNAi. These results establish that EGF inhibits TGF-beta signaling and therefore downregulates tropoelastin expression through the stabilization of Smad corepressor TGIF. We also demonstrated that neutrophil elastase causes stabilization of TGIF through transactivation of the EGFR/Mek/Erk signaling pathway, which is dependent on the release of EGFR ligands.
机译：弹性蛋白的主要成分弹性蛋白可保持成熟肺中气道和血管的弹性和结构完整性。弹性蛋白是非常耐用的聚合物，由其可溶性前体原弹性蛋白的交联单体组装而成。一旦沉积，弹性蛋白在生物体的整个生命周期中基本上不会在健康的肺部翻身。然而，肺气肿的特征是弹性纤维不可逆破坏，这是弹性增加和弹性蛋白修复不足的结果。弹性蛋白修复不足的潜在机制仍在研究中。我们以前曾报道过中性粒细胞弹性蛋白酶通过表皮生长因子受体（EGFR）/丝裂原激活的蛋白激酶激酶（Mek）/细胞外信号调节激酶1和2（Erk）信号传导途径的反式激活而下调大鼠肺成纤维细胞中原弹性蛋白的表达，这取决于表皮生长因子（EGF）样生长因子的释放。在本研究中，我们研究了EGF下调原弹性蛋白表达的机制。我们发现，大鼠胎儿肺成纤维细胞系RFL-6中原弹性蛋白的表达主要是通过自分泌转化生长因子-β（TGF-β）来维持的。我们证明，EGF通过EGFR / Mek / Erk途径通过抑制TGF-β信号传导而下调原弹性蛋白的表达。我们表明，EGF不能阻止TGF-β诱导的Smad2 / 3核积累；它不能阻止Smad2 / 3的积累。相反，EGF通过EGFR / Mek / Erk介导的TGIF磷酸化来稳定Smad核心加压因子TG相互作用因子（TGIF）。我们证实升高的TGIF水平足以抑制TGF-β诱导的原弹性蛋白在RFL-6细胞中的表达。此外，升高的TGIF水平对于EGF下调原弹性蛋白表达至关重要，因为在TGIF水平被RNAi敲低的细胞中，EGF对原弹性蛋白表达的抑制作用得以阻止。这些结果表明，EGF抑制TGF-β信号传导，因此通过稳定Smad核心抑制剂TGIF来下调原弹性蛋白的表达。我们还证明，嗜中性粒细胞弹性蛋白酶通过EGFR / Mek / Erk信号转导途径的反式激活引起TGIF的稳定，这取决于EGFR配体的释放。

著录项

  • 作者

    Yang, Shenghong.;

  • 作者单位

    Boston University.;

  • 授予单位 Boston University.;
  • 学科 Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 211 p.
  • 总页数 211
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;
  • 关键词

  • 入库时间 2022-08-17 11:39:02

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