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PMID: 8460169 Published · ppublish English Journal Article

Mutual regulation of the transcriptional activator NF-kappa B and its inhibitor, I kappa B-alpha.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 90 ·No. 6 ·1993-03-15 ·Pages 2532-6

Brown K, Park S, Kanno T, Franzoso G, Siebenlist U

Abstract

The NK-kappa B transcription factor complex is sequestered in the cytoplasm by the inhibitory protein I kappa B-alpha (MAD-3). Various cellular stimuli relieve this inhibition by mechanisms largely unknown, leading to NF-kappa B nuclear localization and transactivation of its target genes. It is demonstrated here with human T lymphocytes and monocytes that different stimuli, including tumor necrosis factor alpha and phorbol 12-myristate 13-acetate, cause rapid degradation of I kappa B-alpha, with concomitant activation of NF-kappa B, followed by a dramatic increase in I kappa B-alpha mRNA and protein synthesis. Transfection studies reveal that the I kappa B-alpha mRNA and the encoded protein are potently induced by NF-kappa B and by homodimers of p65 and of c-Rel. We propose a model in which NF-kappa B and I kappa B-alpha mutually regulate each other in a cycle: saturating amounts of the inhibitory I kappa B-alpha protein are destroyed upon stimulation, allowing rapid activation of NF-kappa B. Subsequently, I kappa B-alpha mRNA and protein levels are quickly induced by the activated NF-kappa B. This resurgence of I kappa B-alpha protein acts to restore an equilibrium in which NF-kappa B is again inhibited.

MeSH Terms
Blotting, Northern Cell Line Cell Nucleus/drug effects,physiology DNA-Binding Proteins/genetics,metabolism Gene Expression Regulation/drug effects Humans I-kappa B Proteins Ionomycin/pharmacology Macromolecular Substances Monocytes/immunology NF-kappa B/antagonists & inhibitors,metabolism RNA, Messenger/metabolism T-Lymphocytes/immunology Tetradecanoylphorbol Acetate/pharmacology Transfection Tumor Necrosis Factor-alpha/pharmacology
Chemicals
DNA-Binding Proteins I kappa B beta protein I-kappa B Proteins Macromolecular Substances NF-kappa B RNA, Messenger Tumor Necrosis Factor-alpha Ionomycin Tetradecanoylphorbol Acetate
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Brown K
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Park S
Kanno T
Franzoso G
Siebenlist U
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.90.6.2532
Published
1993-03-15
Pages
2532-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC46122
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.90.6.2532 PMC Full Text View journal details
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