c-Jun N-terminal kinase 1 interacts with and negatively regulates Wnt/beta-catenin signaling through GSK3beta pathway
UMass Chan Affiliations
Program in Molecular MedicineDocument Type
Journal ArticlePublication Date
2008-12-01
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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 3beta (GSK3beta) activity. But beta-catenin inhibition was significantly reduced by GSK3beta RNA interference or GSK3beta inhibitor lithium chloride and proteasome inhibitor MG132. Further, mutant beta-catenin at the phosphorylation sites of Ser33 and Ser37 by GSK3beta 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 GSK3beta pathway and that the beta-catenin alteration is probably responsible for the intestinal tumor formation in JNK1-deficient mice.Source
Carcinogenesis. 2008 Dec;29(12):2317-24. doi: 10.1093/carcin/bgn239. Epub 2008 Oct 24. Link to article on publisher's siteDOI
10.1093/carcin/bgn239Permanent Link to this Item
http://hdl.handle.net/20.500.14038/28343PubMed ID
18952597Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1093/carcin/bgn239