RNA-binding protein HuR mediates cytoprotection through stimulation of XIAP translation

Expression of the intrinsic cellular caspase inhibitor XIAP is regulated primarily at the level of protein synthesis. The 5′ untranslated region harbours an Internal Ribosome Entry Site

(IRES) motif that supports cap-independent translation of XIAP mRNA during conditions of cellular stress. In this study, we show that the RNA-binding protein HuR, which is known to

orchestrate an antiapoptotic cellular program, stimulates translation of XIAP mRNA through XIAP IRES. We further show that HuR binds to XIAP IRES in vitro and in vivo, and stimulates

recruitment of the XIAP mRNA into polysomes. Importantly, protection from the apoptosis-inducing agent etoposide by overexpression of HuR requires the presence of XIAP, suggesting that

HuR-mediated cytoprotection is partially executed through enhanced XIAP translation. Our data suggest that XIAP belongs to the HuR-regulated RNA operon of antiapoptotic genes, which, along

with Bcl-2, Mcl-1 and ProTα, contributes to the regulation of cell survival.

We thank Drs Nehal Thakor and Stephen Baird for critical discussions. We are grateful to Drs P Anderson and R Screaton for the gift of anti-TIA-1/TIAR and anti-GST antibodies, respectively,

and to Dr I Gallouzi for the GFP-HuR, GFP-HuR(CP1), GFP-HuR(CP2), AP-HuR-GST, AP-HuR(CP1)-GST and AP-HuR(CP2)-GST overexpression constructs. This work was supported by an operating grant

from the Canadian Institutes of Health Research to MH (CIHR; MOP 89737); MG was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of

Health. MH is the CHEO Volunteer Association Endowed Scholar.

Present address: Current address: Atlantic Cancer Research Institute, Hôtel-Dieu Pavilion, 35 Providence St., Moncton, New Brunswick, Canada E1C 8X3.,

Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada

Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada

Department of Paediatrics, University of Ottawa, Ottawa, Ontario, Canada

Laboratory of Cellular and Molecular Biology, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA

Supplementary Information accompanies the paper on the Oncogene website

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