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Molecular and Cellular Biology, October 2005, p. 8444-8455, Vol. 25, No. 19
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.19.8444-8455.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Kris A. Steinbrecher,1,{dagger} Willie Wilson III,1,2 Patricia C. Cogswell,1 and Albert S. Baldwin1,2,3*

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 {kappa}B (NF-{kappa}B) activity, implying a functional role for GSK-3ß in regulating NF-{kappa}B. Here, we have explored mechanisms by which GSK-3ß 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-3ß activity. Furthermore, nuclear accumulation of p65 following tumor necrosis factor treatment is unaffected by the loss of GSK-3ß. However, NF-{kappa}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-{kappa}B-regulated genes, such as I{kappa}B{alpha} and macrophage inflammatory protein 2, is minimally affected by the absence of GSK-3ß. 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-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-{kappa}B.

* Corresponding author. Mailing address: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7295. Phone: (919) 966-3652. Fax: (919) 966-3652. E-mail: abaldwin{at}med.unc.edu.

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

Molecular and Cellular Biology, October 2005, p. 8444-8455, Vol. 25, No. 19
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.19.8444-8455.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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