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Science 311 (5764): 1141-1146

Copyright © 2006 by the American Association for the Advancement of Science

Molecular Linkage Between the Kinase ATM and NF-{kappa}B Signaling in Response to Genotoxic Stimuli

Zhao-Hui Wu, Yuling Shi, Randal S. Tibbetts, Shigeki Miyamoto*

Abstract: The transcription factor NF-{kappa}B modulates apoptotic responses induced by genotoxic stress. We show that NF-{kappa}B essential modulator (NEMO), the regulatory subunit of I{kappa}B kinase (IKK) (which phosphorylates the NF-{kappa}B inhibitor I{kappa}B), associates with activated ataxia telangiectasia mutated (ATM) after the induction of DNA double-strand breaks. ATM phosphorylates serine-85 of NEMO to promote its ubiquitin-dependent nuclear export. ATM is also exported in a NEMO-dependent manner to the cytoplasm, where it associates with and causes the activation of IKK in a manner dependent on another IKK regulator, a protein rich in glutamate, leucine, lysine, and serine (ELKS). Thus, regulated nuclear shuttling of NEMO links two signaling kinases, ATM and IKK, to activate NF-{kappa}B by genotoxic signals.

Department of Pharmacology, University of Wisconsin–Madison, 301 SMI, 1300 University Avenue, Madison, WI 53706, USA.

* To whom correspondence should be addressed. E-mail: smiyamot{at}wisc.edu

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