Journal Article

Activation of the RON receptor tyrosine kinase attenuates transforming growth factor-β1-induced apoptotic death and promotes phenotypic changes in mouse intestinal epithelial cells

Da Wang, Qi Shen, Xiang-Ming Xu, Yi-Qing Chen and Ming-Hai Wang

in Carcinogenesis

Volume 26, issue 1, pages 27-36
Published in print January 2005 | ISSN: 0143-3334
Published online January 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh284
Activation of the RON receptor tyrosine kinase attenuates transforming growth factor-β1-induced apoptotic death and promotes phenotypic changes in mouse intestinal epithelial cells

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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)-β1. 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-β1. This effect is dependent on RON expression and phosphorylation that inhibit the TGF-β1-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-β1-induced cleavage of caspase-3 and BAD. By protecting cells from apoptotic death, activated RON collaborates with TGF-β1 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-β1 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.

Keywords: mAb, monoclonal antibody; DMEM, Dulbecco's modified Eagle's medium; EMT, epithelial to mesenchymal transition; FBS, fetal bovine serum; MSP, macrophage stimulating protein; RON, recepteur d'origine nantais; si, small interfering; TGF, transforming-growth factor

Journal Article.  6257 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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