The Wnt antagonist Dickkopf-1 is regulated by Bmp signaling and c-Jun and modulates programmed cell death
The Wnt antagonist Dickkopf-1 is regulated by Bmp signaling and c-Jun and modulates programmed cell death
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DOI：
10.1093/emboj/21.5.966
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发表时间：
2002-03-01
期刊：
影响因子：
11.4
通讯作者：
Rüther, U
中科院分区：
文献类型：
--
作者：
Grotewold, L;Rüther, U
Dickkopf-1（Dkk-1）已被证明是一种有效的抑制剂Wnt/β-连环蛋白信号在各种测定和生物体。在这项研究中，我们发现Dkk-1的表达与正常和突变脊椎动物肢体发育中程序性细胞死亡的位点显著重叠，并确定了其上游调控因子，其中之一是Bmp-4。有趣的是，Bmp-4只有在同时诱导细胞凋亡时才激活Dkk-1。此外，Dkk-1是严重上调紫外线照射和其他几种遗传毒性刺激。我们进一步表明Dkk-1的正常表达依赖于Ap-1家族成员c-Jun，并且Dkk-1的过表达增强了脊椎动物肢体中BMP触发的细胞凋亡。综上所述，我们的研究结果提供了Dkk-1介导的Wnt/β-连环蛋白信号抑制在响应不同应激信号中的重要作用的证据，这些应激信号都集中在体内c-Jun的激活上。
Dickkopf-1 (Dkk-1) has been shown to be a potent inhibitor of Wnt/beta-catenin signaling in a variety of assays and organisms. In this study, we show that expression of Dkk-1 overlaps significantly with the sites of programmed cell death in normal as well as mutant vertebrate limb development, and identify several of its upstream regulators, one of which is Bmp-4. Interestingly, Bmp-4 only activates Dkk-1 when it concomitantly induces apoptosis. Moreover, Dkk-1 is heavily up-regulated by UV irradiation and several other genotoxic stimuli. We further show that normal expression of Dkk-1 is dependent on the Ap-1 family member c-Jun and that overexpression of Dkk-1 enhances Bmp-triggered apoptosis in the vertebrate limb. Taken together, our results provide evidence for an important role of Dkk-1-mediated inhibition of Wnt/beta-catenin signaling in response to different stress signals that all converge on the activation of c-Jun in vivo.