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Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation.

Glycogen synthase kinase-3 (GSK-3)-alpha and -beta are closely related protein-serine kinases, which act as inhibitory components of Wnt signalling during embryonic development and cell proliferation in adult tissues. Insight into the physiological function of GSK-3 has emerged from genetic analysis in Drosophila, Dictyostelium and yeast. Here we show that disruption of the murine GSK-3beta gene results in embryonic lethality caused by severe liver degeneration during mid-gestation, a phenotype consistent with excessive tumour necrosis factor (TNF) toxicity, as observed in mice lacking genes involved in the activation of the transcription factor activation NF-kappaB. GSK-3beta-deficient embryos were rescued by inhibition of TNF using an anti-TNF-alpha antibody. Fibroblasts from GSK-3beta-deficient embryos were hypersensitive to TNF-alpha and showed reduced NF-kappaB function. Lithium treatment (which inhibits GSK-3; refs 8, 9) sensitized wild-type fibroblasts to TNF and inhibited transactivation of NF-kappaB. The early steps leading to NF-kappaB activation (degradation of I-kappaB and translocation of NF-kappaB to the nucleus) were unaffected by the loss of GSK-3beta, indicating that NF-kappaB is regulated by GSK-3beta at the level of the transcriptional complex. Thus, GSK-3beta facilitates NF-kappaB function.

Pubmed ID: 10894547


  • Hoeflich KP
  • Luo J
  • Rubie EA
  • Tsao MS
  • Jin O
  • Woodgett JR



Publication Data

July 6, 2000

Associated Grants


Mesh Terms

  • Animals
  • Apoptosis
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Cell Line
  • Cell Survival
  • E-Selectin
  • Enzyme Inhibitors
  • Female
  • Fetal Death
  • Gene Expression Regulation
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinases
  • Lithium
  • Liver Diseases
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutagenesis
  • NF-kappa B
  • Transcription, Genetic
  • Tumor Necrosis Factor-alpha