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PMID: 15923614 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

RelA/p65 regulation of IkappaBbeta.

Molecular and cellular biology ·Vol. 25 ·No. 12 ·2005-06-00 ·Pages 4956-68

Hertlein E, Wang J, Ladner KJ, Bakkar N, Guttridge DC

Abstract

IkappaB inhibitor proteins are the primary regulators of NF-kappaB. In contrast to the defined regulatory interplay between NF-kappaB and IkappaBalpha, much less is known regarding the regulation of IkappaBbeta by NF-kappaB. Here, we describe in detail the regulation of IkappaBbeta by RelA/p65. Using p65(-/-) fibroblasts, we show that IkappaBbeta is profoundly reduced in these cells, but not in other NF-kappaB subunit knockouts. This regulation prevails during embryonic and postnatal development in a tissue-specific manner. Significantly, in both p65(-/-) cells and tissues, IkappaBalpha is also reduced, but not nearly to the same extent as IkappaBbeta, thus highlighting the degree to which IkappaBbeta is dependent on p65. This dependence is based on the ability of p65 to stabilize IkappaBbeta protein from the 26S proteasome, a process mediated in large part through the p65 carboxyl terminus. Furthermore, IkappaBbeta 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 IkappaBbeta, but not IkappaBalpha, causes a severe growth defect associated with apoptosis. Based on these findings, we propose that tight control of IkappaBbeta protein by p65 is necessary for the maintenance of cellular homeostasis.

MeSH Terms
Animals Apoptosis Cell Survival DNA-Binding Proteins/genetics,metabolism Embryo, Mammalian/anatomy & histology,physiology Fibroblasts/cytology,physiology Gene Expression Regulation, Developmental I-kappa B Kinase I-kappa B Proteins/genetics,metabolism Mice Mice, Knockout NF-kappa B/antagonists & inhibitors,genetics,metabolism Proteasome Endopeptidase Complex/metabolism Protein Isoforms/genetics,metabolism Protein Serine-Threonine Kinases/metabolism Protein Structure, Tertiary Serine/metabolism Tissue Distribution Transcription Factor RelA Tumor Necrosis Factor-alpha/genetics,metabolism
Chemicals
DNA-Binding Proteins I kappa B beta protein I-kappa B Proteins NF-kappa B Protein Isoforms Transcription Factor RelA Tumor Necrosis Factor-alpha Serine Protein Serine-Threonine Kinases Chuk protein, mouse I-kappa B Kinase Ikbkb protein, mouse Ikbke protein, mouse Proteasome Endopeptidase Complex ATP dependent 26S protease
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Hertlein Erin
Human Cancer Genetics Program, The Ohio State University, Columbus, OH, USA.
Wang Jingxin
Ladner Katherine J
Bakkar Nadine
Guttridge Denis C
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.25.12.4956-4968.2005
Published
2005-06-00
Pages
4956-68
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1140602
Subset
IM
Grants
NCI NIH HHS · K01 CA097953 · United States
NCI NIH HHS · CA97953 · United States
External Links
PubMed source DOI: 10.1128/MCB.25.12.4956-4968.2005 PMC Full Text View journal details
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