Down-regulation of Sprouty2 via p38 MAPK plays a key role in the induction of cellular apoptosis by tumor necrosis factor-α
Down-regulation of Sprouty2 via p38 MAPK plays a key role in the induction of cellular apoptosis by tumor necrosis factor-α
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DOI：
10.1016/j.bbrc.2008.08.037
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发表时间：
2008-10-24
影响因子：
3.1
通讯作者：
Warburton, David
中科院分区：
文献类型：
--
作者：
Ding, Wei;Warburton, David
哺乳动物Sprouty 2（Spry 2）是受体酪氨酸激酶/ERK信号通路的关键调节因子，并且参与许多生物过程，包括细胞生长、迁移和肿瘤抑制。在这里，我们证明了在小鼠Swiss 3 T3成纤维细胞和MLE 15肺上皮细胞中，Spry 2的细胞内蛋白水平被肿瘤坏死因子-α（TNF-α）显著下调。虽然TNF-α激活多个信号级联，但只有p38 MAPK通路的抑制剂阻断TNF-α诱导的Spry 2下调。此外，由于Spry 2的mRNA水平和蛋白半衰期均未被TNF-α处理改变，这表明可能涉及介导TNF-α抑制作用的翻译机制。重要的是，通过基因过表达挽救了TNF-α诱导的Spry 2的小丑调节，导致了Swiss 3 T3细胞中TNF-α的凋亡效应的逆转。据我们所知，这项研究是第一个报道Spry 2与TNF-α信号通路的关联。(C)2008年爱思唯尔公司All rights reserved.
Mammalian Sprouty2 (Spry2) is a key regulator of the receptor tyrosine kinase/ERK signaling pathway and involved in many biological processes, including cell growth, migration, and tumor suppression. Here, we demonstrated that the intracellular protein level of Spry2 was significantly down-regulated by tumor necrosis factor-alpha (TNF-alpha) in both murine Swiss 3T3 fibroblasts and MLE15 lung epithelial cells. Although TNF-alpha activates multiple signaling cascades, only the inhibitor of p38 MAPK pathway blocked TNF-alpha-induced Spry2 down-regulation. Moreover, since both the mRNA level and protein half-life of Spry2 were unaltered by TNF-alpha treatment, this indicated the possible involvement of a translational mechanism in mediating the inhibitory effect of TNF-alpha. Importantly, rescue of the TNF-alpha-induced clown-regulation of Spry2 by gene overexpression led to reverse of the apoptotic effect of TNF-alpha in Swiss 3T3 cells. To our knowledge, this study is the first that reported the association of Spry2 with TNF-alpha signaling pathway. (C) 2008 Elsevier Inc. All rights reserved.