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Molecular and Cellular Biology, November 2003, p. 8070-8083, Vol. 23, No. 22
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.22.8070-8083.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

I{kappa}B Kinase-Independent I{kappa}B{alpha} Degradation Pathway: Functional NF-{kappa}B Activity and Implications for Cancer Therapy

Vinay Tergaonkar, Virginie Bottero, Masahito Ikawa,{dagger} Qiutang Li, and Inder M. Verma*

Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037

Received 22 April 2003/ Returned for modification 7 July 2003/ Accepted 9 August 2003

Antiapoptotic activity of NF-{kappa}B in tumors contributes to acquisition of resistance to chemotherapy. Degradation of I{kappa}B is a seminal step in activation of NF-{kappa}B. The I{kappa}B kinases, IKK1 and IKK2, have been implicated in both I{kappa}B degradation and subsequent modifications of NF{kappa}B. Using mouse embryo fibroblasts (MEFs) devoid of both IKK1 and IKK2 genes (IKK1/2-/-), we document a novel I{kappa}B degradation mechanism. We show that this degradation induced by a chemotherapeutic agent, doxorubicin (DoxR), does not require the classical serine 32 and 36 phosphorylation or the PEST domain of I{kappa}B{alpha}. Degradation of I{kappa}B{alpha} is partially blocked by phosphatidylinositol 3-kinase inhibitor LY294002 and is mediated by the proteasome. Free NF-{kappa}B generated by DoxR-induced I{kappa}B degradation in IKK1/2-/- cells is able to activate chromatin based NF-{kappa}B reporter gene and expression of the endogenous target gene, I{kappa}B{alpha}. These results also imply that modification of NF-{kappa}B by IKK1 or IKK2 either prior or subsequent to its release from I{kappa}B is not essential for NF-{kappa}B-mediated gene expression at least in response to DNA damage. In addition, DoxR-induced cell death in IKK1/2-/- MEFs is enhanced by simultaneous inhibition of NF-{kappa}B activation by blocking the proteasome activity. These results reveal an additional pathway of activating NF-{kappa}B during the course of anticancer therapy and provide a mechanistic basis for the observation that proteasome inhibitors could be used as adjuvants in chemotherapy.

* Corresponding author. Mailing address: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 453-4100. Fax: (858) 558-7454. E-mail: verma{at}salk.edu.

{dagger} Present address: Genome Information Research Center, Osaka University, 3-1, Yamadaoka, Suita, Osaka 565-0871, Japan.

Molecular and Cellular Biology, November 2003, p. 8070-8083, Vol. 23, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.22.8070-8083.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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