Inhibition of fibroblast growth by Notch1 signaling is mediated by induction of Wnt11-dependent WISP-1.
Inhibition of fibroblast growth by Notch1 signaling is mediated by induction of Wnt11-dependent WISP-1.
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DOI：
10.1371/journal.pone.0038811
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Velazquez OC
中科院分区：
文献类型：
--
作者：
Liu ZJ;Li Y;Tan Y;Xiao M;Zhang J;Radtke F;Velazquez OC
成纤维细胞是基质的组成部分，也是生长因子和细胞外基质（ECM）的重要来源。它们在维持组织稳态和伤口愈合及肿瘤生长中起重要作用。Notch信号调节多种细胞中的生物学功能。为了阐明Notch信号在成纤维细胞中的生理功能，我们在小鼠（Notch 1Flox/Flox）胚胎成纤维细胞（MEFs）中消融Notch 1。Notch 1-缺陷（Notch 1-/-）MEFs显示更快的生长和运动速率相比，Notch 1Flox/Flox MEFs。然而，这种表型变化是可逆的Notch 1激活的Notch 1缺陷的MEFs通过过表达的Notch 1（NICD 1）的细胞内结构域的重建。相比之下，通过将NICD 1引入原代人真皮成纤维细胞（FF 2441）来组成性激活Notch 1信号传导，其引起泛Notch激活，抑制细胞生长和运动性，而当Notch激活被Master-mind样1的显性负突变体（DN-MAML-1）抵消时，细胞抑制是可缓解的。在功能上，“Notch激活的”基质成纤维细胞可以抑制肿瘤细胞生长/侵袭。此外，Notch激活诱导FF 2441细胞中Wnt诱导的分泌蛋白-1（WISP-1/CCN 4）的表达，而MEFs中Notch 1的缺失导致相反的效果。值得注意的是，WISP-1抑制成纤维细胞增殖，并负责介导Notch 1的抑制作用，因为siRNA介导的WISP-1表达阻断可以缓解细胞生长抑制。Notch 1诱导的WISP-1表达似乎是Wnt 11依赖性的，但Wnt 1无关。阻断Wnt 11表达导致WISP-1表达降低，并释放Notch诱导的细胞生长抑制。这些发现表明，Notch途径激活对成纤维细胞增殖的抑制至少部分是通过调节Wnt 1非依赖性但Wnt 11依赖性的WISP-1表达来介导的。
Fibroblasts are an integral component of stroma and important source of growth factors and extracellular matrix (ECM). They play a prominent role in maintaining tissue homeostasis and in wound healing and tumor growth. Notch signaling regulates biological function in a variety of cells. To elucidate the physiological function of Notch signaling in fibroblasts, we ablated Notch1 in mouse (Notch1Flox/Flox) embryonic fibroblasts (MEFs). Notch1-deficient (Notch1 −/−) MEFs displayed faster growth and motility rate compared to Notch1Flox/Flox MEFs. Such phenotypic changes, however, were reversible by reconstitution of Notch1 activation via overexpression of the intracellular domain of Notch1 (NICD1) in Notch1-deficient MEFs. In contrast, constitutive activation of Notch1 signaling by introducing NICD1 into primary human dermal fibroblasts (FF2441), which caused pan-Notch activation, inhibited cell growth and motility, whereas cellular inhibition was relievable when the Notch activation was countered with dominant-negative mutant of Master-mind like 1 (DN-MAML-1). Functionally, “Notch-activated” stromal fibroblasts could inhibit tumor cell growth/invasion. Moreover, Notch activation induced expression of Wnt-induced secreted proteins-1 (WISP-1/CCN4) in FF2441 cells while deletion of Notch1 in MEFs resulted in an opposite effect. Notably, WISP-1 suppressed fibroblast proliferation, and was responsible for mediating Notch1's inhibitory effect since siRNA-mediated blockade of WISP-1 expression could relieve cell growth inhibition. Notch1-induced WISP-1 expression appeared to be Wnt11-dependent, but Wnt1-independent. Blockade of Wnt11 expression resulted in decreased WISP-1 expression and liberated Notch-induced cell growth inhibition. These findings indicated that inhibition of fibroblast proliferation by Notch pathway activation is mediated, at least in part, through regulating Wnt1-independent, but Wnt11-dependent WISP-1 expression.
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