Tremble P, Chiquet-Ehrismann R, Werb Z
Laboratory of Radiobiology and Environmental Health, University of California, San Francisco 94143-0750.
Mol Biol Cell. 1994 Apr;5(4):439-53. doi: 10.1091/mbc.5.4.439.
Tenascin (TN) is a large oligomeric glycoprotein that is present transiently in the extracellular matrix (ECM) of cells and is involved in morphogenetic movements, tissue patterning, and tissue repair. It has multiple domains, both adhesive and anti-adhesive, that interact with cells and with fibronectin (FN) and other ECM macromolecules. We have studied the consequences of the interaction of TN with a FN matrix on gene expression in rabbit synovial fibroblasts. Fibroblasts plated on a mixed substrate of FN and TN, but not on FN alone, upregulated synthesis of four genes: collagenase, stromelysin, the 92-kDa gelatinase, and c-fos. Although the fibroblasts spread well on both FN and FN/TN substrates, nuclear c-Fos increased within 1 h only in cells that were plated on FN/TN. TN did not induce the expression of collagenase in cells plated on substrates of type I collagen or vitronectin (VN). Moreover, soluble TN added to cells adhering to a FN substrate or to serum proteins had no effect, suggesting that TN has an effect only in the context of mixed substrates of FN and TN. Collagenase increased within 4 h of plating on a FN/TN substrate and exhibited kinetics similar to those for induction of collagenase gene expression by signaling through the integrin FN receptor. Arg-Gly-Asp peptide ligands that recognize either the FN receptor or the VN receptor and function-perturbing anti-integrin monoclonal antibodies diminished the interaction of fibroblasts with a mixed substrate of FN, TN, and VN, but had no effect on the adhesion of fibroblasts to a substrate of FN and VN, suggesting that both receptors recognize the complex. Anti-TN68, an antibody that recognizes an epitope in the carboxyl-terminal type III repeats involved in the interaction of TN with both FN and cells, blocked the inductive effect of the FN/TN substrate, whereas anti-TNM1, an antibody that recognizes an epitope in the amino-terminal anti-adhesive region of epidermal growth factor-like repeats, had no effect. These data suggest that transient alteration of the composition of ECM by addition of proteins like TN may regulate the expression of genes involved in cell migration, tissue remodeling, and tissue invasion, in regions of tissue undergoing phenotypic changes.
腱生蛋白（TN）是一种大型寡聚糖蛋白，它短暂存在于细胞外基质（ECM）中，参与形态发生运动、组织模式形成和组织修复。它有多个结构域，既有黏附性的，也有抗黏附性的，能与细胞、纤连蛋白（FN）及其他细胞外基质大分子相互作用。我们研究了TN与FN基质相互作用对兔滑膜成纤维细胞基因表达的影响。接种在FN和TN混合底物上的成纤维细胞，而非仅接种在FN上的成纤维细胞，上调了四个基因的合成：胶原酶、基质溶解素、92-kDa明胶酶和c-fos。尽管成纤维细胞在FN和FN/TN底物上均能良好铺展，但仅接种在FN/TN上的细胞中，核内c-Fos在1小时内就增加了。TN并未在接种于I型胶原或玻连蛋白（VN）底物上的细胞中诱导胶原酶的表达。此外，添加到黏附于FN底物或血清蛋白上的细胞中的可溶性TN没有作用，这表明TN仅在FN和TN的混合底物环境中起作用。接种在FN/TN底物上4小时内胶原酶增加，其动力学与通过整合素FN受体信号传导诱导胶原酶基因表达的动力学相似。识别FN受体或VN受体的精氨酸-甘氨酸-天冬氨酸肽配体以及功能干扰性抗整合素单克隆抗体减少了成纤维细胞与FN、TN和VN混合底物的相互作用，但对成纤维细胞与FN和VN底物的黏附没有影响，这表明两种受体都能识别该复合物。抗TN68是一种识别参与TN与FN及细胞相互作用的羧基末端III型重复序列中表位的抗体，它阻断了FN/TN底物的诱导作用，而识别表皮生长因子样重复序列氨基末端抗黏附区域中表位的抗体抗TNM1则没有作用。这些数据表明，通过添加如TN等蛋白质对细胞外基质组成进行短暂改变，可能在经历表型变化的组织区域中调节参与细胞迁移、组织重塑和组织侵袭的基因表达。
