Sequential Modification of NEMO/IKKγ by SUMO-1 and Ubiquitin Mediates NF-κB Activation by Genotoxic Stress

The transcription factor NF-κB is critical for setting the cellular sensitivities to apoptotic stimuli, including DNA damaging anticancer agents. Central to NF-κB signaling pathways is NEMO/IKKγ, the regulatory subunit of the cytoplasmic IκB kinase (IKK) complex. While NF-κB activation by genotoxic...

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Veröffentlicht in:Cell 2003-11, Vol.115 (5), p.565-576
Hauptverfasser: Huang, Tony T, Wuerzberger-Davis, Shelly M, Wu, Zhao-Hui, Miyamoto, Shigeki
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container_end_page 576
container_issue 5
container_start_page 565
container_title Cell
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creator Huang, Tony T
Wuerzberger-Davis, Shelly M
Wu, Zhao-Hui
Miyamoto, Shigeki
description The transcription factor NF-κB is critical for setting the cellular sensitivities to apoptotic stimuli, including DNA damaging anticancer agents. Central to NF-κB signaling pathways is NEMO/IKKγ, the regulatory subunit of the cytoplasmic IκB kinase (IKK) complex. While NF-κB activation by genotoxic stress provides an attractive paradigm for nuclear-to-cytoplasmic signaling pathways, the mechanism by which nuclear DNA damage modulates NEMO to activate cytoplasmic IKK remains unknown. Here, we show that genotoxic stress causes nuclear localization of IKK-unbound NEMO via site-specific SUMO-1 attachment. Surprisingly, this sumoylation step is ATM-independent, but nuclear localization allows subsequent ATM-dependent ubiquitylation of NEMO to ultimately activate IKK in the cytoplasm. Thus, genotoxic stress induces two independent signaling pathways, SUMO-1 modification and ATM activation, which work in concert to sequentially cause nuclear targeting and ubiquitylation of free NEMO to permit the NF-κB survival pathway. These SUMO and ubiquitin modification pathways may serve as anticancer drug targets.
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subjects ATM protein
IKK^g protein
NEMO protein
SUMO-1 protein
title Sequential Modification of NEMO/IKKγ by SUMO-1 and Ubiquitin Mediates NF-κB Activation by Genotoxic Stress
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