Cellular FLIP inhibits β-catenin ubiquitylation and enhances Wnt signaling
Cellular FLIP inhibits β-catenin ubiquitylation and enhances Wnt signaling
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DOI：
10.1128/mcb.24.19.8418-8427.2004
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发表时间：
2004-10-01
影响因子：
5.3
通讯作者：
Tsuruo, T
中科院分区：
文献类型：
--
作者：
Naito, M;Katayama, R;Tsuruo, T
细胞翻转(cell flip，cFLIP)是caspase 8的同系物，不具有抑制Fas信号转导的caspase活性。CFLIP蛋白通常在人类肿瘤中表达，被认为抑制了涉及Fas系统的抗肿瘤免疫反应。在这里，我们报道了一种长形式的cFlIP(cFlIP-L)抑制β-连环素泛素化，增加内源性胞内β-连环素，导致β-连环素移位到细胞核内，并诱导表达β-连环素的细胞中依赖于连环素的基因表达。用WNT3a刺激稳定表达cFlIP-L的细胞，与对照组相比，Wnt信号增强。相反，内源性cFLIP的耗尽会导致Wnt信号的减少。此外，当将次佳剂量的β-连环素注射到非洲爪哇早期胚胎中时，cFlIP-L可增加次生体轴的形成。RNA干扰下调FADD可消除cFLIP-L诱导的β-连环蛋白依赖性基因表达这些结果表明，cFlIP-L与FADD协同作用，通过抑制蛋白酶体对β-连环素的降解，增强了典型的Wnt信号，从而暗示了除了抑制Fas信号外，与肿瘤发生有关的另一种机制。
Cellular FLIP (cFLIP) is a close homologue of caspase 8 without caspase activity that inhibits Fas signaling. The cFLIP protein is often expressed in human tumors and is believed to suppress antitumor immune responses involving the Fas system. Here, we report that a long form of cFLIP (cFLIP-L) inhibits beta-catenin ubiquitylation and increases endogenous cytosolic beta-catenin, which results in translocation of beta-catenin into nuclei and induction of beta-catenin-dependent gene expression in cFLIP-L-expressing cells. When cells stably expressing cFLIP-L were stimulated with Wnt3a, enhanced Wnt signaling was observed compared with the control cells. Conversely, depletion of endogenous cFLIP results in reduced Wnt signaling. Furthermore, cFLIP-L increases secondary-body axis formation when coinjected with suboptimal doses of beta-catenin into early Xenopus embryos. Down-regulation of FADD by RNA-mediated interference abolishes the beta-catenin-dependent gene expression induced by cFLIP-L. These results indicate that cFLIP-L, in cooperation with FADD, enhances canonical Wnt signaling by inhibiting proteasomal degradation of beta-catenin, thus suggesting an additional mechanism involved with tumorgenesis, in addition to inhibiting Fas signaling.