Carcinogenesis Advance Access published online on October 24, 2008
Carcinogenesis, doi:10.1093/carcin/bgn239
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c-Jun NH2-terminal kinase 1 interacts with and negatively regulates Wnt/β-catenin signaling through GSK3β pathway
1 Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612, USA
2 Zhongnan Hospital and 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 Current address: Department of Pathology, the First Affiliated Hospital and Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
* Corresponding author: Wancai Yang, M.D., Department of Pathology, University of Illinois at Chicago, 840 S Wood Street, Room 130 CSN, Chicago, IL 60612, Tel: (312) 355-4154 Fax: (312) 996-7586, E-mail: wyang06{at}uic.edu
Increasing evidence shows that there is an interaction between mitogen-activated protein kinase (MAPK) 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 JNK1-deficient mice by immunohistochemical staining, and that both β-catenin expression and transcriptional activity were significantly upregulated in JNK1-deficent mouse embryonic fibroblasts (MEFs). However, active JNK1 significantly inhibited β-catenin expression and suppressed β-catenin-mediated transcription 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 co-localization was seen in cellular nuclei and cytoplasm. Taken together, our data provides direct evidence that JNK1 interacts with and negatively regulates β-catenin signaling through GSK3β pathway, and that the β-catenin alteration is likely responsible for the intestinal tumor formation in JNK1-deficient mice.
Key Words: JNK1 • β-catenin • GSK3β • carcinogenesis
Received July 7, 2008; revised October 3, 2008; accepted October 11, 2008.
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