Abstract
The transcription factor NF-kappaB modulates apoptotic responses induced by genotoxic stress. We show that NF-kappaB essential modulator (NEMO), the regulatory subunit of IkappaB kinase (IKK) (which phosphorylates the NF-kappaB inhibitor IkappaB), 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-kappaB by genotoxic signals.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Amino Acid Motifs
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / metabolism*
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Cell Line
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Cell Nucleus / metabolism
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Cytoplasm / metabolism
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DNA Damage*
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DNA-Binding Proteins / metabolism*
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Humans
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I-kappa B Kinase / metabolism*
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I-kappa B Proteins / genetics
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I-kappa B Proteins / metabolism
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NF-kappa B / metabolism
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism*
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RNA Interference
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Recombinant Fusion Proteins / metabolism
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SUMO-1 Protein / metabolism
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Signal Transduction*
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Tumor Suppressor Proteins / metabolism*
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Ubiquitin / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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DNA-Binding Proteins
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ERC1 protein, human
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I-kappa B Proteins
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IKBKG protein, human
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NF-kappa B
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Nerve Tissue Proteins
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Recombinant Fusion Proteins
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SUMO-1 Protein
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Tumor Suppressor Proteins
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Ubiquitin
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases
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I-kappa B Kinase