Stockhausen Marie-Thérése, Sjölund Jonas, Axelson Håkan
Department of Laboratory Medicine, Division of Molecular Medicine, Lund University, University Hospital MAS, Entrance 78, S-205 02 Malmö, Sweden.
Exp Cell Res. 2005 Oct 15;310(1):218-28. doi: 10.1016/j.yexcr.2005.07.011.
Ras and Notch signaling have recently been shown to cooperate in the maintenance of neoplastic transformation. Here, we show that TGFalpha, a known activator of Ras signaling, can drive cell proliferation and at the same time induce the expression of the Notch target Hes-1 in the neuroblastoma cell line SK-N-BE(2)c. The up-regulation of Hes-1 occurred both at the transcriptional and protein levels and by use of EGFR and MEK inhibitors we could show that the Hes-1 response was dependent on activation of the MAP kinase ERK. Blocking Notch activation by gamma-secretase inhibition did not profoundly affect the Hes-1 levels, neither in untreated nor in TGFalpha treated cells. The up-regulation of Hes-1 was associated with down-regulation of its pro-neuronal target gene Hash-1. Taken together, these results show that TGFalpha is a potent mitogen of neuroblastoma cells and suggest a connection between activation of ERK and Hes-1, thus providing a link between the Ras and Notch signaling pathways.
最近研究表明，Ras和Notch信号传导在维持肿瘤转化过程中相互协作。在此，我们发现转化生长因子α（TGFα）作为一种已知的Ras信号激活剂，可驱动神经母细胞瘤细胞系SK-N-BE(2)c增殖，同时诱导Notch靶基因Hes-1的表达。Hes-1的上调在转录水平和蛋白水平均有发生，通过使用表皮生长因子受体（EGFR）和丝裂原活化蛋白激酶（MEK）抑制剂，我们发现Hes-1的反应依赖于丝裂原活化蛋白激酶细胞外调节蛋白激酶（ERK）的激活。无论是在未处理的细胞还是TGFα处理的细胞中，通过γ-分泌酶抑制来阻断Notch激活均未对Hes-1水平产生显著影响。Hes-1的上调与其促神经元靶基因Hash-1的下调相关。综上所述，这些结果表明TGFα是神经母细胞瘤细胞的一种有效促有丝分裂原，并提示ERK激活与Hes-1之间存在联系，从而在Ras和Notch信号通路之间建立了关联。
