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A Wnt–Axin2–GSK3bold beta cascade regulates Snail1 activity in breast cancer cells

 Jong In Yook  ;  Xiao-Yan Li  ;  Ichiro Ota  ;  Casey Hu  ;  Hyun Sil Kim  ;  Nam Hee Kim  ;  So Young Cha  ;  Joo Kyung Ryu  ;  Yoon Jung Choi  ;  Jin Kim  ;  Eric R. Fearon  ;  Stephen J. Weiss 
 NATURE CELL BIOLOGY, Vol.8(12) : 1398-1406, 2006 
Journal Title
Issue Date
Amino Acid Sequence ; Animals ; Axin Protein ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology* ; Cell Nucleus/metabolism ; Chick Embryo ; Cytoplasm/metabolism ; Cytoskeletal Proteins/chemistry ; Cytoskeletal Proteins/metabolism* ; Epithelial Cells/pathology ; Gene Expression Regulation, Neoplastic ; Glycogen Synthase Kinase 3/metabolism* ; Glycogen Synthase Kinase 3 beta ; Humans ; Mesoderm/pathology ; Molecular Sequence Data ; Neoplasm Invasiveness ; Nuclear Export Signals ; Protein Transport ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Snail Family Transcription Factors ; TCF Transcription Factors/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism* ; Tumor Cells, Cultured ; Wnt Proteins/metabolism* ; beta Catenin/metabolism
Accumulating evidence indicates that hyperactive Wnt signalling occurs in association with the development and progression of human breast cancer. As a consequence of engaging the canonical Wnt pathway, a beta-catenin-T-cell factor (TCF) transcriptional complex is generated, which has been postulated to trigger the epithelial-mesenchymal transition (EMT) that characterizes the tissue-invasive phenotype. However, the molecular mechanisms by which the beta-catenin-TCF complex induces EMT-like programmes remain undefined. Here, we demonstrate that canonical Wnt signalling engages tumour cell dedifferentiation and tissue-invasive activity through an Axin2-dependent pathway that stabilizes the Snail1 zinc-transcription factor, a key regulator of normal and neoplastic EMT programmes. Axin2 regulates EMT by acting as a nucleocytoplasmic chaperone for GSK3beta, the dominant kinase responsible for controlling Snail1 protein turnover and activity. As dysregulated Wnt signalling marks a diverse array of cancerous tissue types, the identification of a beta-catenin-TCF-regulated Axin2-GSK3beta-Snail1 axis provides new mechanistic insights into cancer-associated EMT programmes.
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2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실) > 1. Journal Papers
5. Research Institutes (연구소) > Oral Cancer Research Institute (구강종양연구소) > 1. Journal Papers
Yonsei Authors
Kim, Nam Hee(김남희) ORCID logo https://orcid.org/0000-0002-3087-5276
Kim, Jin(김진)
Kim, Hyun Sil(김현실) ORCID logo https://orcid.org/0000-0003-3614-1764
Yook, Jong In(육종인) ORCID logo https://orcid.org/0000-0002-7318-6112
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