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-
B-Dependent Transcription
Kris A. Steinbrecher,1,
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
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 I
B kinase activity and subsequent phosphorylation of I
B
, 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 I
B
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.
* 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.
Present address: Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Childrens 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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Copyright © 2005 by the American Society for Microbiology. All rights reserved.