c-Jun N-terminal kinase 1 interacts with and negatively regulates Wnt/β-catenin signaling through GSK3β pathway
c-Jun N-terminal kinase 1 interacts with and negatively regulates Wnt/β-catenin signaling through GSK3β pathway
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DOI：
10.1093/carcin/bgn239
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发表时间：
2008-12-01
期刊：
影响因子：
4.7
通讯作者：
Yang, Wancai
中科院分区：
文献类型：
--
作者：
Hu, Dong;Fang, Wenfeng;Yang, Wancai
越来越多的证据表明丝裂原活化蛋白激酶与Wnt信号之间存在相互作用，并且它们的相互作用在多种细胞过程中起着重要作用。然而，这两种信号如何相互作用尚不清楚。在这项研究中，我们发现，β-catenin的表达显着增加，在肠正常粘膜和肿瘤的c-Jun N-末端激酶（JNK）1缺陷小鼠的免疫组化染色和β-catenin的表达和转录活性显着上调JNK 1缺陷小鼠胚胎成纤维细胞。然而，活性JNK 1通过增强糖原合成酶激酶3 β（GSK 3 β）活性显著抑制β-连环蛋白表达并抑制β-连环蛋白介导的转录活性。但是，GSK 3 β RNA干扰或GSK 3 β抑制剂氯化锂和蛋白酶体抑制剂MG 132显著降低了β-连环蛋白抑制。此外，突变的β-连环蛋白在丝氨酸33和丝氨酸37的磷酸化位点被GSK 3 β抵抗活化的JNK 1诱导的β-连环蛋白降解。此外，JNK 1和β-连环蛋白之间的物理相互作用，通过免疫沉淀检测，它们的共定位在细胞核和细胞质中。综上所述，我们的数据提供了直接的证据，JNK 1通过GSK 3 β途径与β-连环蛋白信号相互作用并负调节β-连环蛋白信号，并且β-连环蛋白的改变可能是JNK 1缺陷小鼠肠道肿瘤形成的原因。
Increasing evidence shows that there is an interaction between mitogen-activated protein kinase and Wnt signaling and that their interaction plays important roles in a variety of cellular processes. However, how the two signaling interacts is not clear. In this study, we found that beta-catenin expression was strikingly increased in the intestinal normal mucosa and tumors of c-Jun N-terminal kinase (JNK) 1-deficient mice by immunohistochemical staining and that both beta-catenin expression and transcriptional activity were significantly upregulated in JNK1-deficient mouse embryonic fibroblasts. However, active JNK1 significantly inhibited beta-catenin expression and suppressed beta-catenin-mediated transcriptional activity by enhancing glycogen synthase kinase 3 beta (GSK3 beta) activity. But beta-catenin inhibition was significantly reduced by GSK3 beta RNA interference or GSK3 beta inhibitor lithium chloride and proteasome inhibitor MG132. Further, mutant beta-catenin at the phosphorylation sites of Ser33 and Ser37 by GSK3 beta was resistant to activated JNK1-induced beta-catenin degradation. Moreover, the physical interaction between JNK1 and beta-catenin was detected by immunoprecipitation, and their colocalization was seen in cellular nuclei and cytoplasm. Taken together, our data provide direct evidence that JNK1 interacts with and negatively regulates beta-catenin signaling through GSK3 beta pathway and that the beta-catenin alteration is probably responsible for the intestinal tumor formation in JNK1-deficient mice.