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J. Biol. Chem., Vol. 282, Issue 47, 33943-33948, November 23, 2007

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The Deubiquitinating Enzyme USP11 Controls an IB Kinase (IKK)-p53 Signaling Pathway in Response to Tumor Necrosis Factor (TNF)^*

From the Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8510, Japan

Post-translational modification and degradation of proteins by the ubiquitin-proteasome system are key regulatory events in cellular responses to various stimuli. The NF-B signaling pathway is controlled by the ubiquitin-mediated proteolysis. Although mechanisms of ubiquitination in the NF-B pathway have been extensively studied, deubiquitination-mediated regulation of the NF-B signaling remains poorly understood. The present studies show that a deubiquitinating enzyme, USP11, specifically regulates IB kinase (IKK) among the NF-B signaling molecules. Knocking down USP11 attenuates expression of IKK in the transcriptional, but not the post-translational, level. However, down-regulation of USP11 dramatically enhances NF-B activity in response to tumor necrosis factor-, indicating that IKK does not require activation of NF-B. Instead, knock down of USP11 or IKK is associated with abrogation of p53 expression upon exposure to tumor necrosis factor-. In concert with these results, silencing of USP11 is associated with transcriptional attenuation of the p53-responsive genes, such as p21 or Bax. Importantly, the ectopic expression of IKK into cells silenced for USP11 restores p53 expression, demonstrating that USP11 functions as an upstream regulator of an IKK-p53 signaling pathway.

Received for publication, July 31, 2007 , and in revised form, September 26, 2007.

^* This work was supported by grants from the Ministry of Education, Science and Culture of Japan (to K. Y. and Y. M.), the Kowa Life Science Foundation (to K. Y.), the Astellas Foundation for Research on Medical Resources (to K. Y.), and the Japan Leukemia Research Fund (to K. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed. Tel: 81-3-5803-5825; Fax: 81-3-5803-0242. ² To whom correspondence may be addressed. Tel.: 81-3-5803-5826; Fax: 81-3-5803-0242; E-mail: yos.mgen{at}mri.tmd.ac.jp.

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