Journal
CELL BIOLOGY INTERNATIONAL
Volume 26, Issue 5, Pages 463-476Publisher
WILEY
DOI: 10.1006/cbir.2002.0901
Keywords
beta-catenin; LEF-1; DLD1; MDCK; HCE cells; epithelial-mesenchymal transformation
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Funding
- NATIONAL EYE INSTITUTE [R01EY009721] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DENTAL &CRANIOFACIAL RESEARCH [R01DE011142] Funding Source: NIH RePORTER
- NEI NIH HHS [R01-EY09721] Funding Source: Medline
- NIDCR NIH HHS [R01-DE11142] Funding Source: Medline
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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.
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