Negative feedback regulation of Wnt4 signaling by EAF1 and EAF2/U19.
Negative feedback regulation of Wnt4 signaling by EAF1 and EAF2/U19.
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EAF1 和 EAF2/U19 对 Wnt4 信号传导的负反馈调节
DOI：
10.1371/journal.pone.0009118
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发表时间：
2010-02-09
期刊：
影响因子：
3.7
通讯作者：
Xiao W
中科院分区：
文献类型：
--
作者：
Wan X;Ji W;Mei X;Zhou J;Liu JX;Fang C;Xiao W
研究表明EAF家族成员EAF 1和EAF 2/U19在肿瘤和胚胎发生中发挥作用。例如，EAF 2/U19可以作为前列腺癌的肿瘤抑制因子。同时，EAF 2/U19是非洲爪蟾眼睛发育所需的非经典Wnt 4信号通路的下游因子，并且沿着EAF 1，通过Wnt维持而有助于斑马鱼胚胎的会聚和伸展运动。在这里，我们使用斑马鱼胚胎和哺乳动物细胞来证明EAF 1和EAF 2/U19都被Wnt 4（Wnt 4a）上调。此外，我们发现EAF 1和EAF 2/U19通过直接结合Wnt 4启动子抑制Wnt 4表达，如染色质免疫沉淀测定所示。这些发现表明Wnt 4和EAF家族之间存在一个自调节负反馈回路，该回路在斑马鱼和哺乳动物之间是保守的。斑马鱼胚胎的拯救实验表明，早期胚胎发育需要通过反馈回路维持适当水平的Wnt 4a。其他人已经证明，肿瘤抑制因子p63、p73和WT 1正调控Wnt 4表达，而p21具有相反的作用，这表明维持适当的Wnt 4表达对于成人组织稳态和预防肿瘤发生也是至关重要的。因此，控制Wnt 4和EAF蛋白表达的自动调节负反馈环可能在胚胎发育和肿瘤抑制中起重要作用。我们的研究结果提供了第一条令人信服的证据，证明EAF和Wnt 4在体内形成了一个自动调节的负反馈回路。
Previous studies indicated that EAF (ELL-associated factor) family members, EAF1 and EAF2/U19, play a role in cancer and embryogenesis. For example, EAF2/U19 may serve as a tumor suppressor in prostate cancer. At the same time, EAF2/U19 is a downstream factor in the non-canonical Wnt 4 signaling pathway required for eye development in Xenopus laevis, and along with EAF1, contributes to convergence and extension movements in zebrafish embryos through Wnt maintenance. Here, we used zebrafish embryos and mammalian cells to show that both EAF1 and EAF2/U19 were up-regulated by Wnt4 (Wnt4a). Furthermore, we found that EAF1 and EAF2/U19 suppressed Wnt4 expression by directly binding to the Wnt4 promoter as seen in chromatin immunoprecipitation assays. These findings indicate that an auto-regulatory negative feedback loop occurs between Wnt4 and the EAF family, which is conserved between zebrafish and mammalian. The rescue experiments in zebrafish embryos showed that early embryonic development required the maintenance of the appropriate levels of Wnt4a through the feedback loop. Others have demonstrated that the tumor suppressors p63, p73 and WT1 positively regulate Wnt4 expression while p21 has the opposite effect, suggesting that maintenance of appropriate Wnt4 expression may also be critical for adult tissue homeostasis and prevention against tumor initiation. Thus, the auto-regulatory negative feedback loop that controls expression of Wnt4 and EAF proteins may play an important role in both embryonic development and tumor suppression. Our findings provide the first convincing line of evidence that EAF and Wnt4 form an auto-regulatory negative feedback loop in vivo.
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影响因子：
8
作者：
Xiao, W.;Zhang, Q.;Wang, Z.
通讯作者：
Wang, Z.
影响因子：
20.3
作者：
Simone, F;Luo, RT;Thirman, MJ
通讯作者：
Thirman, MJ
影响因子：
11.4
作者：
Maurus, D;Héligon, C;Kühl, M
通讯作者：
Kühl, M
影响因子：
5.3
作者：
Luo, RT;Lavau, C;Thirman, MJ
通讯作者：
Thirman, MJ
DOI：
10.1073/pnas.1834480100
发表时间：
2003-09-16
影响因子：
11.1
作者：
Jordan, BK;Shen, JHC;Vilain, E
通讯作者：
Vilain, E