Endostatin is a potential inhibitor of Wnt signaling.
Endostatin is a potential inhibitor of Wnt signaling.
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DOI：
10.1083/jcb.200203064
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发表时间：
2002-08-05
期刊：
影响因子：
--
通讯作者：
Sokol S
中科院分区：
文献类型：
--
作者：
Hanai J;Gloy J;Karumanchi SA;Kale S;Tang J;Hu G;Chan B;Ramchandran R;Jha V;Sukhatme VP;Sokol S
内皮抑素（Endostatin，ES）是胶原XVIII的一个片段，具有抗血管生成活性.为了深入了解ES介导的信号，我们研究了ES RNA对非洲爪蟾胚胎发生的影响，并观察到与受损Wnt信号一致的发育异常。ES RNA阻断β-连环蛋白诱导的轴复制，部分抑制Wnt依赖性转录，并刺激野生型和“稳定”形式的β-连环蛋白的降解，后者表明ES信号传导不涉及糖原合成酶激酶3。此外，ES使用独立于Siah 1蛋白的途径来靶向β-连环蛋白以进行蛋白酶体介导的降解。ES不能抑制T细胞特异性因子（TCF）-VP 16（TVP）的作用，TVP是一种组成性下游转录激活因子，其作用独立于β-连环蛋白。重要的是，这些数据在内皮细胞和具有突变的腺瘤性结肠息肉病蛋白的DLD-1结肠癌细胞中重复。最后，TVP可逆转ES对内皮细胞迁移和细胞周期的抑制作用。尽管在非洲爪蟾和内皮细胞研究中使用了高水平的ES，并且对β-连环蛋白信号传导的影响是适度的，但这些数据表明，在药理学浓度下，ES可能会影响Wnt信号传导并促进β-连环蛋白降解。
Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. To gain insight into ES-mediated signaling, we studied the effects of ES RNA on Xenopus embryogenesis and observed developmental abnormalities consistent with impaired Wnt signaling. ES RNA blocked the axis duplication induced by β-catenin, partially suppressed Wnt-dependent transcription, and stimulated degradation of both wild-type and “stabilized” forms of β-catenin, the latter suggesting that ES signaling does not involve glycogen synthase kinase 3. Moreover, ES uses a pathway independent of the Siah1 protein in targeting β-catenin for proteasome-mediated degradation. ES failed to suppress the effects of T cell–specific factor (TCF)-VP16 (TVP), a constitutive downstream transcriptional activator that acts independently of β-catenin. Importantly, these data were replicated in endothelial cells and also in the DLD-1 colon carcinoma cells with the mutated adenomatous polyposis coli protein. Finally, suppression of endothelial cell migration and inhibition of cell cycle by ES were reversed by TVP. Though high levels of ES were used in both the Xenopus and endothelial cell studies and the effects on β-catenin signaling were modest, these data argue that at pharmacological concentrations ES may impinge on Wnt signaling and promote β-catenin degradation.
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