ABSTRACT
Loss of glycogen synthase kinase 3β (GSK-3β) in mice results in embryonic lethality via hepatocyte apoptosis. Consistent with this result, cells from these mice have diminished nuclear factor κB (NF-κB) activity, implying a functional role for GSK-3β in regulating NF-κB. Here, we have explored mechanisms by which GSK-3β may control NF-κB function. We show that cytokine-induced IκB kinase activity and subsequent phosphorylation of IκBα, p105, and p65 are not affected by the absence of GSK-3β activity. Furthermore, nuclear accumulation of p65 following tumor necrosis factor treatment is unaffected by the loss of GSK-3β. However, NF-κB DNA binding activity is reduced in GSK-3β null cells and in cells treated with a pharmacological inhibitor of GSK-3. Expression of certain NF-κB-regulated genes, such as IκBα and macrophage inflammatory protein 2, is minimally affected by the absence of GSK-3β. Conversely, we have identified a subset of NF-κB-regulated genes, including those for interleukin-6 and monocyte chemoattractant protein 1, that require GSK-3β for efficient expression. We show that efficient localization of p65 to the promoter regions of the interleukin-6 and monocyte chemoattractant protein 1 genes following tumor necrosis factor alpha treatment requires GSK-3β. Therefore, GSK-3β has profound effects on transcription in a gene-specific manner through a mechanism involving control of promoter-specific recruitment of NF-κB.
The JAK2-Akt-glycogen synthase kinase-3β signaling pathway is involved in toll-like receptor 2-induced monocyte chemoattractant protein-1 regulation
