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Molecular and Cellular Biology, May 2008, p. 3139-3150, Vol. 28, No. 10
0270-7306/08/$08.00+0     doi:10.1128/MCB.01469-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Generation and Activation of Multiple Dimeric Transcription Factors within the NF-{kappa}B Signaling System{triangledown}

Soumen Basak, Vincent Feng-Sheng Shih, and Alexander Hoffmann*

Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California—San Diego, La Jolla, California 92093-0375

Received 14 August 2007/ Returned for modification 10 October 2007/ Accepted 15 February 2008

The NF-{kappa}B signaling pathway regulates the activity of multiple dimeric transcription factors that are generated from five distinct monomers. The availabilities of specific dimers are regulated during cell differentiation and organ development and determine the cell's responsiveness to inflammatory or developmental signals. An altered dimer distribution is a hallmark of many chronic diseases. Here, we reveal that the cellular processes that generate different NF-{kappa}B dimers are highly connected through multiple cross-regulatory mechanisms. First, we find that steady-state expression of RelB is regulated by the canonical pathway and constitutive RelA activity. Indeed, synthesis control of RelB is the major determinant of noncanonical NF-{kappa}B dimer activation. Second, processing, not synthesis, of p100 and p105 is mechanistically linked via competitive dimerization with a limited pool of RelA and RelB. This homeostatic cross-regulatory mechanism determines the availability of the p50- and p52-containing dimers and also of the noncanonical I{kappa}B p100. Our results inform a wiring diagram to delineate NF-{kappa}B dimer formation that emphasizes that inflammatory and developmental signaling cannot be considered separately but are highly interconnected.

* Corresponding author. Mailing address: Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California—San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0375. Phone: (858) 822-4670. Fax: (858) 822-4671. E-mail: ahoffmann{at}ucsd.edu

{triangledown} Published ahead of print on 25 February 2008.

Molecular and Cellular Biology, May 2008, p. 3139-3150, Vol. 28, No. 10
0270-7306/08/$08.00+0     doi:10.1128/MCB.01469-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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  • Suto, H., Katakai, T., Sugai, M., Kinashi, T., Shimizu, A. (2009). CXCL13 production by an established lymph node stromal cell line via lymphotoxin-beta receptor engagement involves the cooperation of multiple signaling pathways. Int Immunol 21: 467-476 [Abstract] [Full Text]  


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