Glycogen synthase kinase 3β functions to specify gene-specific, NF-κB-dependent transcription

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