| First Author | Hoeflich KP | Year | 2000 |
| Journal | Nature | Volume | 406 |
| Issue | 6791 | Pages | 86-90 |
| PubMed ID | 10894547 | Mgi Jnum | J:63274 |
| Mgi Id | MGI:1860704 | Doi | 10.1038/35017574 |
| Citation | Hoeflich KP, et al. (2000) Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation [see comments]. Nature 406(6791):86-90 |
| abstractText | 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. |
