Rettig W J, Erickson H P, Albino A P, Garin-Chesa P
Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
J Cell Sci. 1994 Feb;107 ( Pt 2):487-97.
The extracellular matrix protein tenascin (TN) is expressed with precise temporo-spatial patterns during embryonic and fetal development and is induced in healing wounds, inflammatory lesions and solid tumors. These tissue patterns suggest that TN synthesis may be modulated by soluble factors present in developing tissues or released from injured, inflammatory or neoplastic cells. To characterize the extrinsic control of human TN we examined the effects of several signalling molecules on cultured neural, melanocytic and fibroblastic cells. Results obtained with alpha TN antibodies in enzyme-linked immunosorbent and immunoprecipitation assays indicate that TN expression is tightly regulated in a cell type-specific manner: (1) Primitive neuroectodermal tumor (PNET) cells grown in chemically defined, serum-free media show up to > 100-fold TN induction in response to fibroblast growth factors (aFGF, bFGF, K-FGF) and phorbol ester, independent of changes in cell proliferation or total protein synthesis; no induction is seen in PNET cultures stimulated with serum or other growth and differentiation factors. (2) Normal melanocytes, which require FGF and phorbol ester for survival in vitro, fail to express TN; however, they produce TN following oncogenic transformation. (3) Fibroblasts derived from disparate tissues differ up to 100-fold in basal TN production; for example, fetal lung fibroblasts are TNhigh, but conjunctival fibroblasts derived from the same donors and fetal leptomeningeal cells are TNlow. (4) TNlow fibroblasts treated with interleukin-1, tumor necrosis factor-alpha, and interleukin-4 show up to > 100-fold increased TN secretion and TN incorporation into their extracellular matrix. Transforming growth factor-beta, which acts as an inducer of fibronectin, collagen, and integrin-type matrix receptors, has variable effects on fibroblast TN, ranging from increased deposition in the extracellular matrix of fetal conjunctival fibroblasts to reduced secretion in newborn foreskin fibroblasts. In contrast, FGFs (which are potent fibroblast mitogens), phorbol ester, bone morphogenetic proteins, and several other factors tested produced no discernible effects on fibroblast TN expression. These findings suggest that discrete sets of extrinsic signals modify TN expression in specific cell types, with the effects of a given ligand/receptor system determined by cell type-specific signalling pathways that may be linked to unique cis-regulatory elements of the TN gene. As a result, a limited set of regulatory peptides may produce highly diversified TN distribution patterns in developing and lesional tissues.
细胞外基质蛋白腱生蛋白（TN）在胚胎和胎儿发育过程中以精确的时空模式表达，并在愈合伤口、炎症性病变和实体瘤中被诱导表达。这些组织模式表明，TN的合成可能受发育中组织中存在的可溶性因子或从受损、炎症或肿瘤细胞释放的因子的调节。为了表征人TN的外在调控，我们研究了几种信号分子对培养的神经细胞、黑素细胞和成纤维细胞的影响。在酶联免疫吸附测定和免疫沉淀测定中使用α-TN抗体获得的结果表明，TN的表达以细胞类型特异性方式受到严格调控：（1）在化学成分明确的无血清培养基中生长的原始神经外胚层肿瘤（PNET）细胞，对成纤维细胞生长因子（aFGF、bFGF、K-FGF）和佛波酯有反应，TN诱导高达100倍以上，与细胞增殖或总蛋白合成的变化无关；在用血清或其他生长和分化因子刺激的PNET培养物中未观察到诱导。（2）正常黑素细胞在体外需要FGF和佛波酯才能存活，不表达TN；然而，它们在致癌转化后产生TN。（3）来自不同组织的成纤维细胞在基础TN产生上相差高达100倍；例如，胎儿肺成纤维细胞TN含量高，但来自相同供体的结膜成纤维细胞和胎儿软脑膜细胞TN含量低。（4）用白细胞介素-1、肿瘤坏死因子-α和白细胞介素-4处理的TN含量低的成纤维细胞，TN分泌增加高达100倍以上，且TN整合到其细胞外基质中。转化生长因子-β作为纤连蛋白、胶原蛋白和整合素型基质受体的诱导剂，对成纤维细胞TN有不同影响，从增加胎儿结膜成纤维细胞细胞外基质中的沉积到减少新生儿包皮成纤维细胞中的分泌。相比之下，FGF（强效成纤维细胞有丝分裂原）、佛波酯、骨形态发生蛋白和测试的其他几种因子对成纤维细胞TN表达没有明显影响。这些发现表明，不同的外在信号组在特定细胞类型中修饰TN表达，给定配体/受体系统的作用由可能与TN基因独特顺式调控元件相关的细胞类型特异性信号通路决定。因此，一组有限的调节肽可能在发育和病变组织中产生高度多样化的TN分布模式。
