New targets of beta-catenin signaling in the liver are involved in the glutamine metabolism.
Inappropriate activation of the Wnt/beta-catenin signaling has been implicated in the development of hepatocellular carcinoma (HCC), but exactly how beta-catenin works remains to be elucidated. To identify, in vivo, the target genes of beta-catenin in the liver, we have used the suppression subtractive hybridization technique and transgenic mice expressing an activated beta-catenin in the liver that developed hepatomegaly. We identified three genes involved in glutamine metabolism, encoding glutamine synthetase (GS), ornithine aminotransferase (OAT) and the glutamate transporter GLT-1. By Northern blot and immunohistochemical analysis we demonstrated that these three genes were specifically induced by activation of the beta-catenin pathway in the liver. In different mouse models bearing an activated beta-catenin signaling in the liver known to be associated with hepatocellular proliferation we observed a marked up-regulation of these three genes. The cellular distribution of GS and GLT-1 parallels beta-catenin activity. By contrast no up-regulation of these three genes was observed in the liver in which hepatocyte proliferation was induced by a signal-independent of beta-catenin. In addition, the GS promoter was activated in the liver of GS(+/LacZ) mice by adenovirus vector-mediated beta-catenin overexpression. Strikingly, the overexpression of the GS gene in human HCC samples was strongly correlated with beta-catenin activation. Together, our results indicate that GS is a target of the Wnt/beta-catenin pathway in the liver. Because a linkage of the glutamine pathway to hepatocarcinogenesis has already been demonstrated, we propose that regulation of these three genes of glutamine metabolism by beta-catenin is a contributing factor to liver carcinogenesis.
Cadoret
Axelle
A
Département de Génétique, Développement et Pathologie Moléculaire, Institut Cochin, (INSERM U567, CNRS UMR 8104, Université Paris V), 24 rue du Faubourg St-Jacques, 75014 Paris, France.
Ovejero
Christine
C
Terris
Benoit
B
Souil
Evelyne
E
Lévy
Laurence
L
Lamers
Wouter H
WH
Kitajewski
Jan
J
Kahn
Axel
A
Perret
Christine
C
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D017931:DNA Primers; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics; D005974:Glutamate-Ammonia Ligase / Q000235:genetics; D005973:Glutamine / Q000378:metabolism*; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009953:Ornithine-Oxo-Acid Transaminase / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D015854:Up-Regulation; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D027342:Excitatory Amino Acid Transporter 2; D015534:Trans-Activators; D051176:beta Catenin; D005973:Glutamine; D009953:Ornithine-Oxo-Acid Transaminase; D005974:Glutamate-Ammonia Ligase