title: The transforming growth factor-α and cyclin D1 genes are direct targets of β-catenin signaling in hepatocyte proliferation.
abstract: OBJECTIVE
  β-Catenin is an oncogene frequently mutated in hepatocellular carcinoma. In this study, we investigated target genes of β-catenin signaling in hepatocyte proliferation.
  
  
  METHODS
  We studied transgenic mice displaying either inactivation or activation of the β-catenin pathway, focusing on analysis of liver proliferation due to aberrant β-catenin activation, and on the regeneration process during which β-catenin signaling is transiently activated. We localized in situ the various partners involved in proliferation or identified as targets of β-catenin in these transgenic and regenerating livers. We also performed comparative transcriptome analyses, using microarrays. Finally, we extracted, from deep-sequencing data, both the DNA regulatory elements bound to the β-catenin/Tcf nuclear complex and the expression levels of critical targets identified in microarrays.
  
  
  RESULTS
  β-Catenin activation during liver regeneration occurred during G1/S cell cycle progression and allowed zonal extension of the normal territory of active β-catenin and panlobular proliferation. We found that β-catenin controlled both cell-autonomous and non-cell-autonomous hepatocyte proliferation, through direct transcriptional and complex control of cyclin D1 gene expression and of the expression of a new target gene, Tgfα.
  
  
  CONCLUSIONS
  We propose that β-catenin controls panlobular hepatocyte proliferation partly by controlling, together with its Tcf4 nuclear partner, expression of the pro-proliferation cyclin D1 and Tgfα genes. This study constitutes a first step toward understanding the oncogenic properties of this prominent signaling pathway in the liver.
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS UMR 8104 Paris, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Torre
authors.forename: Samira
authors.initials: S
authors.lastname: Benhamouche
authors.forename: Claudia
authors.initials: C
authors.lastname: Mitchell
authors.forename: Cécile
authors.initials: C
authors.lastname: Godard
authors.forename: Philippe
authors.initials: P
authors.lastname: Veber
authors.forename: Franck
authors.initials: F
authors.lastname: Letourneur
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cagnard
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jacques
authors.forename: Laetitia
authors.initials: L
authors.lastname: Finzi
authors.forename: Christine
authors.initials: C
authors.lastname: Perret
authors.forename: Sabine
authors.initials: S
authors.lastname: Colnot
mesh_terms: D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle; D049109:Cell Proliferation; D004247:DNA / Q000235:genetics; D020869:Gene Expression Profiling; D019940:Genes, bcl-1; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism*; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism; D008115:Liver Regeneration / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000235:genetics*; D051176:beta Catenin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D016211:Transforming Growth Factor alpha; D051176:beta Catenin; D004247:DNA