Journal
EXPERIMENTAL CELL RESEARCH
Volume 314, Issue 6, Pages 1351-1366Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2007.12.015
Keywords
TNF-alpha; Wnt; NF-kappa B; AP-1; CREB; beta-catenin; glycogen synthase kinase-3; hepatocyte; liver; apoptosis
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Glycogen synthase kinase-3 (GSK-3) is known to modulate cell survival and apoptosis through multiple intracellular signaling pathways. However, its hepatoprotective function and its role in activation of NF-kappa B and anti-apoptotic factors are poorly understood and remain controversial. Here we investigated whether inhibition of GSK-3 could induce apoptosis in the presence of TNF-alpha in primary mouse hepatocytes. We show that pharmacological inhibition of GSK-3 in primary mouse hepatocytes does not lead to TNF alpha-induced apoptosis despite reduced NF-kappa B activity. Enhanced stability of IKB-alpha appears to be responsible for lower levels of nuclear NF-kappa B and hence reduced transactivation. Additionally, inhibition of GSK-3 was accompanied by marked upregulation of beta-catenin, AP-1, and CREB transcription factors. Stimulation of canonical Wnt signaling and CREB activity led to elevated levels of anti-apoptotic factors. Hence, survival of primary mouse hepatocytes may be caused by the activation and/or upregulation of other key regulators of liver homeostasis and regeneration. These signaling molecules may compensate for the compromised anti-apoptotic function of NF-kappa B and allow survival of hepatocytes in the presence of TNF-alpha and GSK-3 inhibition. (C) 2008 Elsevier Inc. All rights reserved.
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