Journal Article

c-Jun N-terminal kinase 1 interacts with and negatively regulates Wnt/β-catenin signaling through GSK3β pathway

Dong Hu, Wenfeng Fang, Anjia Han, Lindsay Gallagher, Roger J. Davis, Bin Xiong and Wancai Yang

in Carcinogenesis

Volume 29, issue 12, pages 2317-2324
Published in print December 2008 | ISSN: 0143-3334
Published online October 2008 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgn239
c-Jun N-terminal kinase 1 interacts with and negatively regulates Wnt/β-catenin signaling through GSK3β pathway

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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 β-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 β-catenin expression and transcriptional activity were significantly upregulated in JNK1-deficient mouse embryonic fibroblasts. However, active JNK1 significantly inhibited β-catenin expression and suppressed β-catenin-mediated transcriptional activity by enhancing glycogen synthase kinase 3β (GSK3β) activity. But β-catenin inhibition was significantly reduced by GSK3β RNA interference or GSK3β inhibitor lithium chloride and proteasome inhibitor MG132. Further, mutant β-catenin at the phosphorylation sites of Ser33 and Ser37 by GSK3β was resistant to activated JNK1-induced β-catenin degradation. Moreover, the physical interaction between JNK1 and β-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 β-catenin signaling through GSK3β pathway and that the β-catenin alteration is probably responsible for the intestinal tumor formation in JNK1-deficient mice.

Journal Article.  4980 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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