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Molecular and Cellular Biology, June 2005, p. 4956-4968, Vol. 25, No. 12
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.12.4956-4968.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

RelA/p65 Regulation of I{kappa}Bß

Erin Hertlein,1,2 Jingxin Wang,1 Katherine J. Ladner,1 Nadine Bakkar,1,3 and Denis C. Guttridge1,2,3,4,5*

Human Cancer Genetics Program,1 Department of Molecular Virology, Immunology and Medical Genetics,4 Integrated Biomedical Graduate Program,2 Molecular, Cellular, and Developmental Biology Graduate Program,3 The Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio5

Received 2 December 2004/ Returned for modification 19 January 2005/ Accepted 17 March 2005

I{kappa}B inhibitor proteins are the primary regulators of NF-{kappa}B. In contrast to the defined regulatory interplay between NF-{kappa}B and I{kappa}B{alpha}, much less is known regarding the regulation of I{kappa}Bß by NF-{kappa}B. Here, we describe in detail the regulation of I{kappa}Bß by RelA/p65. Using p65–/– fibroblasts, we show that I{kappa}Bß is profoundly reduced in these cells, but not in other NF-{kappa}B subunit knockouts. This regulation prevails during embryonic and postnatal development in a tissue-specific manner. Significantly, in both p65–/– cells and tissues, I{kappa}B{alpha} is also reduced, but not nearly to the same extent as I{kappa}Bß, thus highlighting the degree to which I{kappa}Bß is dependent on p65. This dependence is based on the ability of p65 to stabilize I{kappa}Bß protein from the 26S proteasome, a process mediated in large part through the p65 carboxyl terminus. Furthermore, I{kappa}Bß was found to exist in both a basally phosphorylated and a hyperphosphorylated form. While the hyperphosphorylated form is less abundant, it is also more stable and less dependent on p65 and its carboxyl domain. Finally, we show that in p65–/– fibroblasts, expression of a proteolysis-resistant form of I{kappa}Bß, but not I{kappa}B{alpha}, causes a severe growth defect associated with apoptosis. Based on these findings, we propose that tight control of I{kappa}Bß protein by p65 is necessary for the maintenance of cellular homeostasis.

* Corresponding author. Mailing address: Division of Human Cancer Genetics, 420 W. 12th Avenue, The Ohio State University College of Medicine, Columbus, OH 43210. Phone: (614) 688-3137. Fax: (614) 688-4006. E-mail: guttridge-1{at}medctr.osu.edu.

Molecular and Cellular Biology, June 2005, p. 4956-4968, Vol. 25, No. 12
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.12.4956-4968.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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