Negative feedback loop of Wnt signaling through upregulation of conductin/Axin2 in colorectal and liver tumors
Negative feedback loop of Wnt signaling through upregulation of conductin/Axin2 in colorectal and liver tumors
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DOI：
10.1128/mcb.22.4.1184-1193.2002
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发表时间：
2002-02-01
影响因子：
5.3
通讯作者：
Behrens, J
中科院分区：
文献类型：
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作者：
Lustig, B;Jerchow, B;Behrens, J
通过β -连环蛋白/TCF复合物激活Wnt信号是多种肿瘤，特别是结直肠癌和肝脏肿瘤发展的关键事件。Wnt信号由负调节因子传导/axin2/axil控制，传导/axin2/axil通过与肿瘤抑制因子APC和丝氨酸/苏氨酸激酶gsk3 β的功能相互作用诱导β -catenin的降解。本研究表明，在β -catenin/Wnt信号诱导的人类肿瘤中，传导蛋白表达上调，即在结直肠和肝脏肿瘤中发现高水平的传导蛋白和mRNA，而在相应的正常组织中则没有。在其他各种肿瘤类型中，传导素水平在肿瘤组织和正常组织之间没有差异。在Min小鼠apc缺陷肠肿瘤中也观察到传导蛋白的上调。TCF显性阴性突变体对Wnt信号的抑制下调了DLD1结直肠肿瘤细胞中的传导蛋白，但未下调相关蛋白轴蛋白。相反，Wnt-1或凌乱激活Wnt信号分别增加MDA MB 231和Neuro2A细胞的传导水平。在时间过程实验中，β -连环蛋白的稳定先于Wnt-1对传导的上调。这些结果表明，传导是Wnt信号通路的一个靶点。传导上调可能构成一个控制Wnt信号活动的负反馈回路。
Activation of Wnt signaling through beta-catenin/TCF complexes is a key event in the development of various tumors, in particular colorectal and liver tumors. Wnt signaling is controlled by the negative regulator conductin/axin2/axil, which induces degradation of beta-catenin by functional interaction with the tumor suppressor APC and the serine/threonine kinase GSK3beta. Here we show that conductin is upregulated in human tumors that are induced by beta-catenin/Wnt signaling, i.e., high levels of conductin protein and mRNA were found in colorectal and liver tumors but not in the corresponding normal tissues. In various other tumor types, conductin levels did not differ between tumor and normal tissue. Upregulation of conductin was also observed in the APC-deficient intestinal tumors of Min mice. Inhibition of Wnt signaling by a dominant-negative mutant of TCF downregulated conductin but not the related protein, axin, in DLD1 colorectal tumor cells. Conversely, activation of Wnt signaling by Wnt-1 or dishevelled increased conductin levels in MDA MB 231 and Neuro2A cells, respectively. In time course experiments, stabilization of beta-catenin preceded the upregulation of conductin by Wnt-1. These results demonstrate that conductin is a target of the Wnt signaling pathway. Upregulation of conductin may constitute a negative feedback loop that controls Wnt signaling activity.