Carcinogenesis Advance Access originally published online on September 24, 2004
Carcinogenesis 2005 26(1):27-36; doi:10.1093/carcin/bgh284
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Carcinogenesis vol.26 no.1 © Oxford University Press 2005; all rights reserved.
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Activation of the RON receptor tyrosine kinase attenuates transforming growth factor-ß1-induced apoptotic death and promotes phenotypic changes in mouse intestinal epithelial cells
1 Laboratory of Cheung-Kong Scholars Program for Biomedical Sciences, Institute of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China and 2 Department of Pharmaceutical Sciences and Center for Cancer Biology, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, TX 79106, USA
3 To whom correspondence should be addressed Email: minghai.wang{at}ttuhsc.edu
The RON (recepteur d'origine nantais) receptor belongs to the MET proto-oncogene family that is implicated in the oncogenesis of the gastrointestinal epithelium. The present study aimed to determine the role of RON in regulating epithelial phenotypes in response to transforming growth factor (TGF)-ß1. Expression and activation of RON in SV40-immortalized mouse intestinal epithelial MODE-K cells result in reduction of cellular sensitivities towards apoptotic signals elicited by TGF-ß1. This effect is dependent on RON expression and phosphorylation that inhibit the TGF-ß1-induced activation of caspase-3 and truncation of BAD. Among cellular signaling components, the activation of MAP kinase is critical in the RON-mediated inhibitory effect. PD98059, a specific MAP kinase inhibitor, prevented RON-mediated anti-apoptotic activities. PD98059 also prevented the inhibitory effect of RON on TGF-ß1-induced cleavage of caspase-3 and BAD. By protecting cells from apoptotic death, activated RON collaborates with TGF-ß1 in the induction of cell morphological changes with decreased E-cadherin expression and increased migration and morphogenesis. Thus, RON expression and activation modulate phenotypes of gastrointestinal epithelial cells in response to TGF-ß1 with reduced sensitivity to apoptosis and increased migration. These activities might represent a mechanism by which RON activation increases tumorigenic activities and facilitates the progression of transformed epithelial cells towards malignancy.
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