Regulation of mRNAs for type-1 plasminogen activator inhibitor, fibronectin, and type I procollagen by transforming growth factor-beta. Divergent responses in lung fibroblasts and carcinoma cells.
Regulation of mRNAs for type-1 plasminogen activator inhibitor, fibronectin, and type I procollagen by transforming growth factor-beta. Divergent responses in lung fibroblasts and carcinoma cells.
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DOI：
10.1016/s0021-9258(18)69042-8
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发表时间：
1988-03
期刊：
影响因子：
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通讯作者：
J. Keski‐oja;R. Raghow;M. Sawdey;D. Loskutoff;A. Postlethwaite;A. Kang;H. Moses
中科院分区：
文献类型：
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作者：
J. Keski‐oja;R. Raghow;M. Sawdey;D. Loskutoff;A. Postlethwaite;A. Kang;H. Moses
转化生长因子-β（TGF β）是一种生长调节剂，其刺激成纤维细胞的生长，但作为上皮来源细胞的强生长抑制剂。TGF β还影响培养细胞的细胞外基质蛋白和蛋白酶及蛋白酶抑制剂的产生。一种重要的蛋白酶抑制剂是1型纤溶酶原激活物抑制剂（派-1），其产生迅速受到TGF β的影响。为了研究派-1和细胞外基质之间的关系，我们分析了TGF β对恶性人肺癌细胞（A549）和人肺成纤维细胞（WI-38）中派-1、纤连蛋白和I型前胶原的调节。通过多肽分析和通过北方杂交测量相应mRNA的稳态水平来检查相应基因的表达。在两种细胞系中，派-1的mRNA水平被TGF β迅速升高。这种诱导发生在放线菌酮的存在下，因此不依赖于蛋白质的合成。事实上，TGF β和放线菌酮对派-1 mRNA的影响是相加的。与此相反，诱导纤连蛋白，β-肌动蛋白，和I型前胶原（合成仅在WI-38细胞）被废除放线菌酮。总的来说，在这两种细胞类型中，TGF β对纤连蛋白、肌动蛋白和I型前胶原mRNA的稳态mRNA水平的影响相似。然而，派-1 mRNA的产生在两种细胞类型中不同，在癌细胞中是瞬时的（5小时内达到峰值），在成纤维细胞中更持久。因此，肺成纤维细胞和癌细胞之间的派-1 mRNA的TGF β调节的主要差异是作用的持续时间。这些结果，与以前的数据一起，表明派-1和纤溶酶原激活剂可能被TGF β相反地调节。因此，我们提出了一个模型TGF β在细胞外蛋白水解活性的调节。
Transforming growth factor-beta (TGF beta) is a growth modulator which stimulates the growth of fibroblasts but acts as a strong growth inhibitor for cells of epithelial origin. TGF beta also influences the production of extracellular matrix proteins and of proteases and protease inhibitors by cultured cells. One important protease inhibitor whose production is affected rapidly by TGF beta is the type-1 plasminogen activator inhibitor (PAI-1). To investigate the relationships between PAI-1 and the extracellular matrix, we analyzed the regulation by TGF beta of PAI-1, fibronectin, and type I procollagen in malignant human lung carcinoma cells (A549) and in human lung fibroblasts (WI-38). The expression of the respective genes was examined by polypeptide analyses and by measurements of the steady-state levels of the corresponding mRNAs by Northern hybridization. The mRNA levels for PAI-1 were elevated rapidly by TGF beta in both cell lines. This induction occurred in the presence of cycloheximide and thus was not dependent on protein synthesis. In fact, the effects of TGF beta and cycloheximide on PAI-1 mRNA were additive. In contrast, the induction of fibronectin, beta-actin, and type I procollagen (synthesized only in WI-38 cells) was abrogated by cycloheximide. In general, the effects of TGF beta on the steady-state levels of mRNAs for fibronectin, actin, and type I procollagen mRNA were similar in the two cell types. However, the production of PAI-1 mRNA in response to TGF beta differed in the two cell types, being transient (peak within 5 h) in the carcinoma cells and more persistent in fibroblasts. Thus, the major difference in TGF beta regulation of PAI-1 mRNA between lung fibroblasts and carcinoma cells was the duration of the effect. These results, together with previous data, suggest that PAI-1 and plasminogen activators may be regulated oppositely by TGF beta. We therefore propose a model for TGF beta in the regulation of extracellular proteolytic activity.