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Glycogen Synthase Kinase 3ß Functions To Specify Gene-Specific, NF-B-Dependent Transcription

Kris A. Steinbrecher,^1, Willie Wilson III,^1,2 Patricia C. Cogswell,¹ and Albert S. Baldwin^1,2,3*

Lineberger Comprehensive Cancer Center,¹ Curriculum in Genetics and Molecular Biology,² Department of Biology, University of North Carolina, Chapel Hill, North Carolina 27599³

Received 21 February 2005/ Returned for modification 20 April 2005/ Accepted 14 July 2005

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

Present address: Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229.

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