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cIAP1, cIAP2, and XIAP act cooperatively via nonredundant pathways to regulate genotoxic stress-induced nuclear factor-kappaB activation.

cIAP1, cIAP2, and XIAP act cooperatively via nonredundant pathways to regulate genotoxic stress-induced nuclear factor-kappaB activation.

Authors :
Jin HS
Lee DH
Kim DH
Chung JH
Lee SJ
Lee TH
Source :
Cancer research [Cancer Res] 2009 Mar 01; Vol. 69 (5), pp. 1782-91. Date of Electronic Publication: 2009 Feb 17.
Publication Year :
2009

Abstract

Various genotoxic agents cause monoubiquitination of NEMO/IKKgamma-the regulatory subunit of IkappaB kinase (IKK) complex-in the nucleus. Ubiquitinated NEMO exits from the nucleus and forms a complex with the IKK catalytic subunits IKKalpha and IKKbeta, resulting in IKK activation and, ultimately, nuclear factor-kappaB (NF-kappaB) activation. Thus, NEMO ubiquitination is a prerequisite for IKK-dependent activation of NF-kappaB. However, the IKK activation mechanism is unknown and the NEMO-ubiquitinating E3 enzyme has not been identified. We found that inhibitors of apoptosis protein (IAP) regulate genotoxic stress-induced NF-kappaB activation at different levels. XIAP mediates activation of the upstream IKK kinase, TAK1, and couples activated TAK1 to the IKK complex. This XIAP-dependent event occurs in response to camptotechin or etoposide/VP16; however, XIAP is dispensable for activation of NF-kappaB by doxorubicin, which engages a MEK-ERK pathway to activate IKK. We also show that cIAP1 mediates NEMO ubiquitination and cIAP2 regulates an event downstream of NEMO ubiquitination. Our study highlights nonredundant cooperative contributions of IAPs to antiapoptotic NF-kappaB activation by genotoxic signals beyond their classic caspase inhibitory functions.

Details

Language :
English
ISSN :
1538-7445
Volume :
69
Issue :
5
Database :
MEDLINE
Journal :
Cancer research
Publication Type :
Academic Journal
Accession number :
19223549
Full Text :
https://doi.org/10.1158/0008-5472.CAN-08-2256