Direct evidence for a. role of β-catenin/LEF-1 signaling pathway in induction of EMT

被引:386
作者
Kim, K [1 ]
Lu, ZF [1 ]
Hay, ED [1 ]
机构
[1] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA
关键词
beta-catenin; LEF-1; DLD1; MDCK; HCE cells; epithelial-mesenchymal transformation;
D O I
10.1006/cbir.2002.0901
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Epithelial-mesenchymal transformation (EMT) is an important process in development that is characterized by loss of E-cadherin, beta-catenin relocalization, and acquisition of elongated cell shape and ability to invade ECM. beta-catenin has been shown to activate LEF-1 transcription during EMT induced in vitro by c-Fos. Here, we ask whether or not LEF-1 directly introduced into epithelial cells in an adenovirus construct can induce EMT. In normal epithelial cell lines, such as HCE and MDCK cells, that contain functional APC, nuclear beta-catenin induced by exogenous LEF-1 is rapidly exported and EMT is not induced. Leptomycin-B blocks beta-catenin nuclear export, but no EMT occurs due to toxicity. Addition of Wnt-1 to normal epithelial cell lines stabilizes cytoplasmic beta-catenin that LEF-1 then transports to nuclei, causing a small amount of EMT. Our experiments demonstrated, however, that overexpressed LEF-1 upregulates nuclear beta-catenin and promotes dramatic EMT in DLD-1 epithelial tumors that retain nuclear beta-catenin. This EMT is reversible if the LEF-1 virus is removed. Thus, our results demonstrate that LEF-1 can induce EMT directly when its transcription activity is activated by stable nuclear beta-catenin. Normal adult epithelial cells appear to use APC to keep beta-catenin out of the nucleus, thereby avoiding pathologies such as metastases due to LEF/beta-catenin-induced EMT. (C) 2002 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:463 / 476
页数:14
相关论文
共 39 条
[1]   beta-catenin is a target for the ubiquitin-proteasome pathway [J].
Aberle, H ;
Bauer, A ;
Stappert, J ;
Kispert, A ;
Kemler, R .
EMBO JOURNAL, 1997, 16 (13) :3797-3804
[2]  
ARAKISASAKI K, 1995, INVEST OPHTH VIS SCI, V36, P614
[3]   NH2-terminal deletion of beta-catenin results in stable colocalization of mutant beta-catenin with adenomatous polyposis coli protein and altered MDCK cell adhesion [J].
Barth, AIM ;
Pollack, AL ;
Altschuler, Y ;
Mostov, KE ;
Nelson, WJ .
JOURNAL OF CELL BIOLOGY, 1997, 136 (03) :693-706
[4]   DISSECTING TUMOR-CELL INVASION - EPITHELIAL-CELLS ACQUIRE INVASIVE PROPERTIES AFTER THE LOSS OF UVOMORULIN-MEDIATED CELL CELL-ADHESION [J].
BEHRENS, J ;
MAREEL, MM ;
VANROY, FM ;
BIRCHMEIER, W .
JOURNAL OF CELL BIOLOGY, 1989, 108 (06) :2435-2447
[5]   Functional interaction of beta-catenin with the transcription factor LEF-1 [J].
Behrens, J ;
vonKries, JP ;
Kuhl, M ;
Bruhn, L ;
Wedlich, D ;
Grosschedl, R ;
Birchmeier, W .
NATURE, 1996, 382 (6592) :638-642
[6]   LOSS OF EPITHELIAL DIFFERENTIATION AND GAIN OF INVASIVENESS CORRELATES WITH TYROSINE PHOSPHORYLATION OF THE E-CADHERIN BETA-CATENIN COMPLEX IN CELLS TRANSFORMED WITH A TEMPERATURE-SENSITIVE V-SRC GENE [J].
BEHRENS, J ;
VAKAET, L ;
FRIIS, R ;
WINTERHAGER, E ;
VANROY, F ;
MAREEL, MM ;
BIRCHMEIER, W .
JOURNAL OF CELL BIOLOGY, 1993, 120 (03) :757-766
[7]   DISSOCIATION OF MADIN-DARBY CANINE KIDNEY EPITHELIAL-CELLS BY THE MONOCLONAL-ANTIBODY ANTI-ARC-1 - MECHANISTIC ASPECTS AND IDENTIFICATION OF THE ANTIGEN AS A COMPONENT RELATED TO UVOMORULIN [J].
BEHRENS, J ;
BIRCHMEIER, W ;
GOODMAN, SL ;
IMHOF, BA .
JOURNAL OF CELL BIOLOGY, 1985, 101 (04) :1307-1315
[8]  
Birchmeier C, 1996, ACTA ANAT, V156, P217
[9]   Induction and regulation of epithelial-mesenchymal transitions [J].
Boyer, B ;
Vallés, AM ;
Edme, N .
BIOCHEMICAL PHARMACOLOGY, 2000, 60 (08) :1091-1099
[10]   β-catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer [J].
Brabletz, T ;
Jung, A ;
Dag, S ;
Hlubek, F ;
Kirchner, T .
AMERICAN JOURNAL OF PATHOLOGY, 1999, 155 (04) :1033-1038