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Molecular and Cellular Biology, November 2004, p. 9317-9326, Vol. 24, No. 21
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.21.9317-9326.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Tumor Necrosis Factor Alpha Induction of NF-{kappa}B Requires the Novel Coactivator SIMPL

Hyung-Joo Kwon,1,{dagger} Erin Haag Breese,1 Eva Vig-Varga,1 Yong Luo,1 Younghee Lee,2,{dagger} Mark G. Goebl,1 and Maureen A. Harrington1*

Departments of Biochemistry and Molecular Biology,1 Microbiology and Immunology, Indiana University School of Medicine, Indiana University Cancer Center and Walther Cancer Institute, Indianapolis, Indiana2

Received 27 April 2004/ Returned for modification 7 June 2004/ Accepted 6 August 2004

A myriad of stimuli including proinflammatory cytokines, viruses, and chemical and mechanical insults activate a kinase complex composed of I{kappa}B kinase ß (IKK-ß), IKK-{alpha}, and IKK-{gamma}/N, leading to changes in NF-{kappa}B-dependent gene expression. However, it is not clear how the NF-{kappa}B response is tailored to specific cellular insults. Signaling molecule that interacts with mouse pelle-like kinase (SIMPL) is a signaling component required for tumor necrosis factor alpha (TNF-{alpha})-dependent but not interleukin-1-dependent NF-{kappa}B activation. Herein we demonstrate that nuclear localization of SIMPL is required for type I TNF receptor-induced NF-{kappa}B activity. SIMPL interacts with nuclear p65 in a TNF-{alpha}-dependent manner to promote endogenous NF-{kappa}B-dependent gene expression. The interaction between SIMPL and p65 enhances p65 transactivation activity. These data support a model in which TNF-{alpha} activation of NF-{kappa}B dependent-gene expression requires nuclear relocalization of p65 as well as nuclear relocalization of SIMPL, generating a TNF-{alpha}-specific induction of gene expression.

* Corresponding author. Mailing address: Department of Biochemistry & Molecular Biology, 635 Barnhill Dr., MS 4071, Indianapolis, IN 46202-5122. Phone: (317) 274-7527. Fax: (317) 274-4686. E-mail: mharrin{at}iupui.edu.

{dagger} Present address: Institute of Life Science & Biotechnology, Yonsei University, Seoul 120-749, South Korea.

Molecular and Cellular Biology, November 2004, p. 9317-9326, Vol. 24, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.21.9317-9326.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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