TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors.
TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors.
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DOI：
10.1083/jcb.127.6.2021
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发表时间：
1994-12
期刊：
影响因子：
--
通讯作者：
Derynck R
中科院分区：
文献类型：
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作者：
Miettinen PJ;Ebner R;Lopez AR;Derynck R
分泌的多肽转化生长因子-β (TGF-β) 通过 I 型和 II 型细胞表面受体发挥其多种活性。在上皮细胞中，TGF-β信号转导途径的激活导致细胞增殖的抑制和细胞外基质产生的增加。 TGF-β在发育过程中广泛表达，其生物活性与上皮-间质相互作用有关，例如肺、肾和乳腺的分支形态发生，以及乳腺上皮和间质之间的诱导事件。在本研究中，我们在体外研究了 TGF-β 对小鼠乳腺上皮细胞的影响。 TGF-β 可逆地诱导正常乳腺上皮 NMuMG 细胞从上皮表型向成纤维细胞表型分化的改变。细胞形态的变化与 (a) 上皮标志物 E-钙粘蛋白、ZO-1 和桥粒斑蛋白 I 和 II 的表达减少相关； (b) 间充质标志物的表达增加，例如纤连蛋白； (c) 肌动蛋白纤维的成纤维细胞样重组。这种表型分化显示出上皮间质转分化事件的标志。由于 NMuMG 细胞产生高水平的 I 型 TGF-β 受体 Tsk7L，但缺乏据报道介导 TGF-β 反应性的 ALK-5/R4 I 型受体的表达，因此我们评估了 Tsk7L 受体在 TGF-β 介导的转分化中的作用。我们生成的 NMuMG 细胞稳定地过表达截短的 Tsk7L I 型受体，该受体缺乏大部分胞质激酶结构域，因此充当显性失活突变体。这些转染细胞在暴露于 TGF-β 后不再经历上皮到间质的形态变化，但仍然表现出一些 TGF-β 介导的反应。我们得出结论，TGF-β能够调节E-钙粘蛋白表达并诱导上皮细胞中可逆的上皮间质转分化。与其他转分化生长因子（例如 bFGF 和 HGF）不同，这些变化伴随着生长抑制。我们的结果还表明 Tsk7L I 型受体介导 TGF-β 诱导的上皮间质转化。
The secreted polypeptide transforming growth factor-beta (TGF-beta) exerts its multiple activities through type I and II cell surface receptors. In epithelial cells, activation of the TGF-beta signal transduction pathways leads to inhibition of cell proliferation and an increase in extracellular matrix production. TGF-beta is widely expressed during development and its biological activity has been implicated in epithelial-mesenchymal interactions, e.g., in branching morphogenesis of the lung, kidney, and mammary gland, and in inductive events between mammary epithelium and stroma. In the present study, we investigated the effects of TGF-beta on mouse mammary epithelial cells in vitro. TGF-beta reversibly induced an alteration in the differentiation of normal mammary epithelial NMuMG cells from epithelial to fibroblastic phenotype. The change in cell morphology correlated with (a) decreased expression of the epithelial markers E- cadherin, ZO-1, and desmoplakin I and II; (b) increased expression of mesenchymal markers, such as fibronectin; and (c) a fibroblast-like reorganization of actin fibers. This phenotypic differentiation displays the hallmarks of an epithelial to mesenchymal transdifferentiation event. Since NMuMG cells make high levels of the type I TGF-beta receptor Tsk7L, yet lack expression of the ALK-5/R4 type I receptor which has been reported to mediate TGF-beta responsiveness, we evaluated the role of the Tsk7L receptor in TGF-beta- mediated transdifferentiation. We generated NMuMG cells that stably overexpress a truncated Tsk7L type I receptor that lacks most of the cytoplasmic kinase domain, thus function as a dominant negative mutant. These transfected cells no longer underwent epithelial to mesenchymal morphological change upon exposure to TGF-beta, yet still displayed some TGF-beta-mediated responses. We conclude that TGF-beta has the ability to modulate E-cadherin expression and induce a reversible epithelial to mesenchymal transdifferentiation in epithelial cells. Unlike other transdifferentiating growth factors, such as bFGF and HGF, these changes are accompanied by growth inhibition. Our results also implicate the Tsk7L type I receptor as mediating the TGF-beta-induced epithelial to mesenchymal transition.