Carcinogenesis Advance Access originally published online on October 24, 2008
Carcinogenesis 2008 29(12):2317-2324; doi:10.1093/carcin/bgn239
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c-Jun N-terminal kinase 1 interacts with and negatively regulates Wnt/β-catenin signaling through GSK3β pathway
1 Department of Pathology, University of Illinois at Chicago, 840 S Wood Street, Room 130 CSN, Chicago, IL 60612, USA
2 Open Laboratory for Oversea Scientists, Wuhan University, Wuhan 430071, China
3 Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
4 Department of Oncology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China
5 Present address: Department of Pathology, First Affiliated Hospital and Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
* To whom correspondence should be addressed. Tel: +1 312 355 4154; Fax: +1 312 996 7586; Email: wyang06{at}uic.edu
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.
Abbreviations: APC, adenomatous polyposis coli; GSK3β, glycogen synthase kinase 3β; HA, hemagglutinin; HEK, human embryonic kidney; JNK, c-Jun N-terminal kinase; LiCl, lithium chloride; MAPK, mitogen-activated protein kinase; MEF, mouse embryonic fibroblast; PBS, phosphate-buffered saline; RNAi, RNA interference; TCF, T-cell factor; UV, ultraviolet
Received July 7, 2008; revised October 3, 2008; accepted October 11, 2008.
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