title: Beta-catenin-NF-κB interactions in murine hepatocytes: a complex to die for.
abstract: Wnt/β-catenin signaling plays an important role in hepatic homeostasis, especially in liver development, regeneration, and cancer, and loss of β-catenin signaling is often associated with increased apoptosis. To elucidate how β-catenin may be regulating hepatocyte survival, we investigated the susceptibility of β-catenin conditional knockout (KO) mice and their wild-type (WT) littermates to Fas and tumor necrosis factor-α (TNF-α), two common pathways of hepatocyte apoptosis. While comparable detrimental effects from Fas activation were observed in WT and KO, a paradoxical survival benefit was observed in KO mice challenged with D-galactosamine/lipopolysaccharide. KO mice showed significantly lower morbidity and liver injury due to early, robust, and protracted activation of NF-κB in the absence of β-catenin. Enhanced NF-κB activation in KO mice was associated with increased basal inflammation and Toll-like receptor 4 expression and lack of the p65/β-catenin complex in hepatocytes. The p65/β-catenin complex in WT livers underwent temporal dissociation allowing for NF-κB activation to regulate hepatocyte survival following TNF-α-induced hepatic injury. Decrease of total β-catenin protein but not its inactivation induced p65 activity, whereas β-catenin stabilization either chemically or due to mutations repressed it in hepatomas in a dose-dependent manner, whereas β-catenin stabilization repressed it either chemically or due to mutations.
  
  
  CONCLUSIONS
  The p65/β-catenin complex in hepatocytes undergoes dynamic changes during TNF-α-induced hepatic injury and plays a critical role in NF-κB activation and cell survival. Modulation of β-catenin levels is a unique mode of regulating NF-κB activity and thus may present novel opportunities in devising therapeutics in specific hepatic injuries.
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA. knnst5@pitt.edu
authors.forename: Kari
authors.initials: K
authors.lastname: Nejak-Bowen
authors.forename: Alexander
authors.initials: A
authors.lastname: Kikuchi
authors.forename: Satdarshan P S
authors.initials: SP
authors.lastname: Monga
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury / Q000503:physiopathology*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology; D051996:Transcription Factor RelA / Q000502:physiology; D051176:beta Catenin / Q000235:genetics / Q000502:physiology; D019014:fas Receptor / Q000502:physiology
chemical_list: C491899:Fas protein, mouse; D008070:Lipopolysaccharides; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D051176:beta Catenin; D019014:fas Receptor