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J. Biol. Chem., Vol. 279, Issue 5, 3509-3515, January 30, 2004

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Nuclear Role of IB Kinase-/NF-B Essential Modulator (IKK/NEMO) in NF-B-dependent Gene Expression^*

Udit N. Verma, Yumi Yamamoto, Shashi Prajapati, and Richard B. Gaynor

From the Division of Hematology-Oncology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8594

The IB kinase (IKK) complex, which is composed of the two kinases IKK and IKK and the regulatory subunit IKK/nuclear factor-B (NF-B) essential modulator (NEMO), is important in the cytokine-induced activation of the NF-B pathway. In addition to modulation of IKK activity, the NF-B pathway is also regulated by other processes, including the nucleocytoplasmic shuttling of various components of this pathway and the post-translational modification of factors bound to NF-B-dependent promoters. In this study, we explored the role of the nucleocytoplasmic shuttling of components of the IKK complex in the regulation of the NF-B pathway. IKK/NEMO was demonstrated to shuttle between the cytoplasm and the nucleus and to interact with the nuclear coactivator cAMP-responsive element-binding protein-binding protein (CBP). Using both in vitro and in vivo analysis, we demonstrated that IKK/NEMO competed with p65 and IKK for binding to the N terminus of CBP, inhibiting CBP-dependent transcriptional activation. These results indicate that, in addition to the key role of IKK/NEMO in regulating cytokine-induced IKK activity, its ability to shuttle between the cytoplasm and the nucleus and to bind to CBP can lead to transcriptional repression of the NF-B pathway.

Received for publication, August 21, 2003 , and in revised form, October 27, 2003.

^* 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.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Div. of Hematology-Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8594. Tel.: 317-651-5134; Fax: 317-277-3652; E-mail: gaynor_richard{at}lilly.com.

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