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

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

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 IB kinase ß (IKK-ß), IKK-, and IKK-/N, leading to changes in NF-B-dependent gene expression. However, it is not clear how the NF-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-)-dependent but not interleukin-1-dependent NF-B activation. Herein we demonstrate that nuclear localization of SIMPL is required for type I TNF receptor-induced NF-B activity. SIMPL interacts with nuclear p65 in a TNF--dependent manner to promote endogenous NF-B-dependent gene expression. The interaction between SIMPL and p65 enhances p65 transactivation activity. These data support a model in which TNF- activation of NF-B dependent-gene expression requires nuclear relocalization of p65 as well as nuclear relocalization of SIMPL, generating a TNF--specific induction of gene expression.

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

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