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

Abstract

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.

Current insights into the regulation of programmed cell death by NF-κB

“…Altered NF-kB recruitment to promoters Phosphorylation of RelA by GSK3b has emerged as another important regulatory mechanism for NF-kB's protective activity, as GSK3b knockout mice die from massive liver apoptosis similar to that seen in mice deficient for RelA, IKKb or NEMO (Bonnard et al, 2000;Hoeflich et al, 2000). Interestingly, GSK3b appears to regulate NF-kB's protective activity by promoting efficient recruitment of RelA to gene-specific promoters (Steinbrecher et al, 2005).…”

Glycogen synthase kinase-3β is a crucial mediator of signal-induced RelB degradation

“…The phenotype of GSK-3b-deficient mice (Hoeflich et al, 2000) is strikingly similar to the phenotype displayed by IKK-b-or RelA-deficient mice and characterized by embryonic death caused by increased apoptosis in the liver (Beg et al, 1995;Li et al, 1999). Moreover, mouse embryonic fibroblasts derived from these animals are more sensitive towards tumour necrosis factor-a-induced apoptosis than wildtype fibroblasts because of the inability of these mouse embryonic fibroblasts to induce NF-kB (Hoeflich et al, 2000). Another study demonstrated that GSK-3b has profound effects on NF-kB-mediated transcription in a gene-specific manner through a mechanism involving control of promoter-specific NF-kB recruitment (Steinbrecher et al, 2005).…”

Unraveling MCL-1 degradation

“…13,14 However, this effect may be cell type and pathway specific as paradoxically the lethality observed in the GSK-3b-deficient embryos was due to enhanced liver apoptosis. 15 Although little is known about GSK-3 isoformspecific function, the two family members are not redundant since disruption of GSK-3b resulted in embryonic lethality despite expression of GSK-3a. 15 …”

“…15 Although little is known about GSK-3 isoformspecific function, the two family members are not redundant since disruption of GSK-3b resulted in embryonic lethality despite expression of GSK-3a. 15 …”