Participation of NF‐κB in cell survival or proliferation is regulated by interaction with β‐catenin (398.7)

Abstract

Understanding the signaling pathways involved in liver regeneration (LR) has important therapeutic implications. We have previously shown that β‐catenin sequestration of p65 in cytosol prevents it from translocating to the nucleus, and that lack of p65/β‐catenin complex in hepatocyte‐specific β‐catenin knockout (KO) mice enhances survival. To determine whether this association regulates cell proliferation, wild‐type (WT) and KO mice were treated with GalN/LPS to induce liver injury. Proliferation in WT liver occurs during the early phase of injury, but is absent at time of morbidity. Conversely KO display scant proliferation until the “recovery” phase, and an increase in pro‐survival target genes. We then characterized the association and expression of NF‐κB and β‐catenin after LR by immunoprecipitation and demonstrated translocation and interaction of these two proteins in the nucleus within hours after partial hepatectomy (PH), which preceded a 2.5‐fold increase in cyclin‐D1 mRNA. Finally, Hep3B hepatoma cells demonstrated a significant decrease in cyclin‐D1 reporter activity when treated with β‐catenin siRNA but not with p65 siRNA, indicating that while β‐catenin is required for proliferation, p65 may be dispensable. Thus, β‐catenin is an important component of balancing the context‐dependent pro‐proliferation versus pro‐survival function of NF‐κB.