Requirement for glycogen synthase kinase-3β in cell survival and NF-κB activation

Klaus P. Hoeflich, Juan Luo, Elizabeth A. Rubie, Ming-Sound Tsao, Ou Jin and James R. Woodgett ()
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Klaus P. Hoeflich: Ontario Cancer Institute/Princess Margaret Hospital
Juan Luo: Ontario Cancer Institute/Princess Margaret Hospital
Elizabeth A. Rubie: Ontario Cancer Institute/Princess Margaret Hospital
Ming-Sound Tsao: Ontario Cancer Institute/Princess Margaret Hospital
Ou Jin: Ontario Cancer Institute/Princess Margaret Hospital
James R. Woodgett: Ontario Cancer Institute/Princess Margaret Hospital

Nature, 2000, vol. 406, issue 6791, 86-90

Abstract: Abstract Glycogen synthase kinase-3 (GSK-3)-α and -β are closely related protein-serine kinases, which act as inhibitory components of Wnt signalling during embryonic development and cell proliferation in adult tissues1,2. Insight into the physiological function of GSK-3 has emerged from genetic analysis in Drosophila3,4, Dictyostelium 5 and yeast6,7. Here we show that disruption of the murine GSK-3β 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-κB. GSK-3β-deficient embryos were rescued by inhibition of TNF using an anti-TNF-α antibody. Fibroblasts from GSK-3β-deficient embryos were hypersensitive to TNF-α and showed reduced NF-κB function. Lithium treatment (which inhibits GSK-3; refs 8, 9) sensitized wild-type fibroblasts to TNF and inhibited transactivation of NF-κB. The early steps leading to NF-κB activation (degradation of I-κB and translocation of NF-κB to the nucleus) were unaffected by the loss of GSK-3β, indicating that NF-κB is regulated by GSK-3β at the level of the transcriptional complex. Thus, GSK-3β facilitates NF-κB function.

Date: 2000
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DOI: 10.1038/35017574

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