Premium
Regulation of p65‐β‐catenin Complex And Its Targets in Liver Injury And Regeneration
Author(s) -
NejakBowen Kari,
Cornuet Pamela K,
Monga Satdarshan P
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.516.2
Subject(s) - cyclin d1 , wnt signaling pathway , catenin , microbiology and biotechnology , liver regeneration , chemistry , tumor necrosis factor alpha , apoptosis , cancer research , beta catenin , signal transduction , biology , cell cycle , endocrinology , biochemistry , regeneration (biology)
We have previously reported the identification of a complex between β‐catenin and the p65 subunit of NF‐κB. Further, we have shown that β‐catenin sequesters p65 in the cytosol to prevent it from translocating to the nucleus, and that lack of p65‐β‐catenin complex in liver‐specific β‐catenin knockout (KO1) mice enhances survival due to enhanced p65 nuclear translocation and activation. To determine the signaling pathways regulating this complex during acute liver injury, we injected galactosamine (GalN) followed by lipopolysaccharide (LPS), which activates the TNF‐α pathway, into liver‐specific LRP5‐6 double KO mice (KO2) and wild‐type littermate controls (WT). Unlike KO1, KO2 phenocopy WT and show comparable morbidity, apoptosis, liver weight to body weight ratio, and alanine aminotransferase (ALT) levels. This is due to existence of the β‐catenin‐p65 complex in KO2 as opposed to its absence in KO1. These observations also suggest that the β‐catenin‐p65 association is autonomous of Wnt signaling since lack of LRP5‐6 in hepatocytes prevents Wnt communication to β‐catenin. Treatment of Hep3B hepatoma cells with TNF‐α, or of WT mice with GalN/LPS, induced dissociation of the β‐catenin‐p65 complex, implicating TNF‐α signaling in the regulation of this association. Since cyclin D1 is a target of both NF‐κB and β‐catenin, we next examined the role of the p65‐β‐catenin complex in hepatocyte proliferation. In hepatoma cells, TNF‐α induced p65 reporter activity; however, it had no effect on either TOPflash or cyclin D1 reporter. Further, while β‐catenin suppression decreased both cyclin D1 reporter activity and cell proliferation, these functions were unchanged in the presence of p65 siRNA. We then characterized the association and expression of NF‐κB and β‐catenin during liver regeneration and demonstrated translocation of these two proteins in the nucleus within hours after partial hepatectomy, which preceded a 2.5‐fold increase in cyclin‐D1 mRNA. However, using inducible NF‐κB lacZ reporter mice, we found p65 activity to be confined exclusively to the NPC compartment during liver regeneration. Thus we conclude that hepatocyte proliferation is independent of p65 but requires β‐catenin, and that p65 and β‐catenin activation are occurring in disparate cell types during early liver regeneration. The distinct roles of β‐catenin and p65 in proliferation and survival, respectively, offer opportunities for manipulation of this complex to optimize regenerative therapies. Support or Funding Information This study was funded b y NIH grants 1R01DK62277 to SPSM and by the American Liver Foundation's Thomas E. Starzl, MD Postdoctoral Research Fellowship to KNB.