Requirement for glycogen synthase kinase-3β in cell survival and NF-κB 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(1,2). Insight into the physiological function of GSK-3 has emerged from genetic analysis in Drosophila(3,4), Dictyostelium(5) and yeast(6,7). Here we show that disruption of the murine GSK-3 beta 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-kappa B. GSK-3 beta-dercient embryos were rescued by inhibition of TNF using an anti-TNF-alpha antibody. Fibroblasts from GSK-3b-dercient embryos were hypersensitive to TNF-alpha and showed reduced NF-kappa B function. Lithium treatment (which inhibits GSK-3; refs 8, 9) sensitized wild-type fibroblasts to TNF and inhibited transactivation of NF-kappa B. The early steps leading to NF-kappa B activation (degradation of I-kappa B and translocation of NF-kappa B to the nucleus) were unaffected by the loss of GSK-3b, indicating that NF-kappa B is regulated by GSK-3b at the level of the transcriptional complex. Thus, GSK-3b facilitates NF-kappa B function.