Viral FLIP enhances Wnt signaling downstream of stabilized β-catenin, leading to control of cell growth
Viral FLIP enhances Wnt signaling downstream of stabilized β-catenin, leading to control of cell growth
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DOI：
10.1128/mcb.25.21.9249-9258.2005
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发表时间：
2005-11-01
影响因子：
5.3
通讯作者：
Yonehara, S
中科院分区：
文献类型：
--
作者：
Nakagiri, S;Murakami, A;Yonehara, S
死亡受体介导的细胞凋亡被病毒FLIP（FLICE/胱天蛋白酶8抑制蛋白）有效抑制，其由两个串联重复的死亡效应结构域（DED）组成，通过减少胱天蛋白酶原8的活化。在这里，我们表明，马疱疹病毒2编码的病毒FLIP E8增强Wnt/β-连环蛋白信号在各种细胞系。E8显示出显著增加Wnt 3a信号传导，如T细胞因子/β-连环蛋白的荧光素酶测定和通过诱导内源性细胞周期蛋白D1所示。在死亡受体介导的细胞凋亡中，E8的作用不依赖于其与含DED的信号分子（包括caspase 8和FADD）的直接结合活性。E8增强了稳定的β-连环蛋白下游的Wnt信号传导，而长形式的细胞FLIP（c-FLIPL）增强了293 T细胞中β-连环蛋白的稳定性。因此，E8和c-FLIPL的共表达协同增加了293 T细胞中的Wnt信号传导。此外，E8介导的Wnt信号刺激在未转化细胞系中诱导了显着的生长迟缓，但在转化细胞系中却没有。因此，病毒FLIP E8不仅抑制死亡受体介导的细胞凋亡，而且增强与个体发生和肿瘤发生密切相关的Wnt信号通路。
Death receptor-mediated apoptosis is potently inhibited by viral FLIP (FLICE/caspase 8 inhibitory protein), which is composed of two tandemly repeated death effector domains (DEDs), through reduced activation of procaspase 8. Here, we show that equine herpesvirus 2-encoded viral FLIP E8 enhances Wnt/beta-catenin signaling in a variety of cell lines. E8 was shown to strikingly augment Wnt3a signaling, as shown both in a luciferase assay for T-cell factor/beta-catenin and through induction of endogenous cyclin D1. The effect of E8 was independent of its direct binding activity with DED-containing signaling molecules, including caspase 8 and FADD, in death receptor-mediated apoptosis. E8 enhanced Wnt signaling downstream of stabilized beta-catenin, while a long form of cellular FLIP (c-FLIPL) enhanced stabilization of beta-catenin in 293T cells. Consequently, coexpression of E8 and c-FLIPL synergistically increased Wnt signaling in 293T cells. Moreover, E8-mediated stimulation of Wnt signaling induced dramatic growth retardation in untransformed cell lines but not in transformed cell lines. Thus, viral FLIP E8 not only inhibits death receptor-mediated apoptosis but also enhances Wnt signaling pathways that are closely related to those of both ontogenesis and oncogenesis.