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cIAP1, cIAP2, and XIAP Act Cooperatively via Nonredundant Pathways to Regulate Genotoxic Stress–Induced Nuclear Factor-B Activation

¹ Department of Biology, College of Life Science and Biotechnology and ² Protein Network Research Center, Yonsei University, Seoul, Republic of Korea

Requests for reprints: Tae H. Lee, Department of Biology, College of Life Science and Biotechnology, Yonsei University, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-749, Republic of Korea. Phone: 82-2-2123-4084; Fax: 82-2-312-5657; E-mail: thlee{at}yonsei.ac.kr.

Key Words: IAP • Genotoxic stress • NF-B • TAK1 • Ubiquitination

Various genotoxic agents cause monoubiquitination of NEMO/IKK—the regulatory subunit of IB kinase (IKK) complex—in the nucleus. Ubiquitinated NEMO exits from the nucleus and forms a complex with the IKK catalytic subunits IKK and IKKβ, resulting in IKK activation and, ultimately, nuclear factor-B (NF-B) activation. Thus, NEMO ubiquitination is a prerequisite for IKK-dependent activation of NF-B. 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-B 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-B 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-B activation by genotoxic signals beyond their classic caspase inhibitory functions. [Cancer Res 2009;69(5):1782–91]