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.
Hoeflich
K P
KP
Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Canada.
Luo
J
J
Rubie
E A
EA
Tsao
M S
MS
Jin
O
O
Woodgett
J R
JR
D000818:Animals; D017209:Apoptosis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D019040:E-Selectin / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005313:Fetal Death / Q000235:genetics; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D008094:Lithium / Q000494:pharmacology; D008107:Liver Diseases / Q000196:embryology / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016296:Mutagenesis; D016328:NF-kappa B / Q000378:metabolism*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D019040:E-Selectin; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D008094:Lithium; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3