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J. Biol. Chem., Vol. 283, Issue 8, 5081-5089, February 22, 2008

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Nuclear Tumor Necrosis Factor Receptor-associated Factor 6 in Lymphoid Cells Negatively Regulates c-Myb-mediated Transactivation through Small Ubiquitin-related Modifier-1 Modification^*

Lan V. Pham, Hai-Jun Zhou, Yen-Chiu Lin-Lee, Archito T. Tamayo, Linda C. Yoshimura, Lingchen Fu, Bryant G. Darnay, and Richard J. Ford¹

From the Departments of Hematopathology and Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an adaptor/scaffold protein that mediates several important signaling pathways, including the tumor necrosis factor-R:NF-B pathway, involved in immune surveillance, inflammation, etc. Because most studies of TRAF6 function have focused primarily on its role as an adaptor molecule in signaling pathways in the cytoplasm, the potential functions of TRAF6 in other cellular compartments has not been previously investigated. Here, we demonstrate that TRAF6 resides not only in the cellular cytoplasm but is also found in the nuclei of both normal and malignant B lymphocytes. TRAF6 does not possess a nuclear localization signal but enters the nucleus through the nuclear pore complex containing RanGap1. Chromatin immunoprecipitation cloning experiments demonstrated that nuclear TRAF6 associates with c-Myb within the 5'-end of the c-Myb promoter. Further analysis showed that nuclear TRAF6 is modified by small ubiquitin-related modifier-1, interacts with histone deacetylase 1, and represses c-Myb-mediated transactivation. Thus, TRAF6 negatively regulates c-Myb through a novel repressor function in the nuclei of both normal and malignant B-lymphocytes that could represent a novel control mechanism that maintains cell homeostasis and immune surveillance.

Received for publication, July 31, 2007 , and in revised form, December 12, 2007.

^* This work was supported by the Odyssey Program and the Kimberly-Clark Foundation Award for Scientific Achievement at The University of Texas M. D. Anderson Cancer Center (to L. V. P.) and by NCI, National Institutes of Health Grants CA-RO1-100836 (to R. J. F.) and CA-16672-26 (Cancer Center Support Grant) and a grant from the Lymphoma Research Foundation (to R. J. F.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: Dept. of Hematopathology, Box 54, The University of Texas of M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-792-3121; Fax: 713-792-4840; E-mail: rford{at}mdanderson.org.

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