Published online before print April 1, 2008

This Article Full Text (Rapid PDF) Supplemental Material All Versions of this Article: ajpath.2008.070793v1 172/5/1238    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by del Castillo, G. Articles by Sánchez, A. PubMed PubMed Citation Articles by del Castillo, G. Articles by Sánchez, A.

Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070793

Accepted for publication January 25, 2008.

Article

Deletion of the Met Tyrosine Kinase in Liver Progenitor Oval Cells Increases Sensitivity to Apoptosis in Vitro

Gaelle del Castillo^*, Valentina M. Factor, Margarita Fernández^*, Alberto Álvarez-Barrientos, Isabel Fabregat, Snorri S. Thorgeirsson, and Aránzazu Sánchez^*@

From the Department Bioquímica y Biología Molecular II,* Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain; Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute/National Institutes of Health, Bethesda, Maryland; Unidad de Citometría, Fundación Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain; Fundació Institut d'Investigació Biomèdica de Bellvitge, Centre d'Oncologia Molecular, L'Hospitalet, Barcelona, Spain

^@ To whom correspondence should be addressed. E-mail: munozas{at}farm.ucm.es.

	Abstract

The hepatocyte growth factor (HGF)/Met signaling system is essential for liver development, homeostasis, and function. In this study, we took advantage of a liver-specific, Met-conditional knockout mouse generated in our laboratory to address the molecular mechanisms of HGF/Met signaling in adult liver progenitor cell (oval cell) biology. For this purpose, we isolated oval cells from 3,5-diethoxycarbonyl-1,4-dihydro-collidine-treated Met^flx/flx mice and established oval cell-derived cell lines that carried either functional (Met^flx/flx) or a nonfunctional (Met^-/-) met gene using virus-mediated Cre-loxP recombination. Oval cells lacking Met tyrosine kinase activity displayed neither Met phosphorylation nor activation of downstream targets and were refractory to HGF stimulation. Although Met^-/- and Met^flx/flx cells proliferated at similar rates under 10% serum, Met-deficient cells demonstrated decreased cell viability and were more prone to apoptosis when challenged with either serum starvation or the pro-apoptotic cytokine transforming growth factor-. Treatment with HGF reduced transforming growth factor--mediated cell death in Met^flx/flx but not Met^-/- cells. Importantly, Met^flx/flx and Met^-/- cells both constitutively expressed hgf, and conditioned medium from serum-starved oval cells exhibited anti-apoptotic activity in Met^flx/flx cells. Furthermore, serum-starved Met^flx/flx cells showed persistent activation of the Met tyrosine kinase, suggesting HGF/Met autocrine regulation. In conclusion, these data reveal a critical, functional role for Met in oval cell survival through an autocrine mechanism.