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Author Notes:

Correspondence: Muxiang Zhou, M.D., Division of Pediatric Hematology/Oncology, Emory University School of Medicine, 2015 Uppergate Drive, Atlanta, GA 30322;. Telephone: 404-727-1426; Fax: 404-727-4455; Email: mzhou@emory.edu

Acknowledgments: We are most grateful to Dr. Martin Holcik and Dr. Richard E. Lloyd for providing us with the bicistronic plasmid pβgal-XIAP-CAT and dicistronic plasmid pRL-XIAP-FL, respectively.

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Research Funding:

This work was supported by grants from NIH (R01 CA123490), The Leukemia and Lymphoma Society (6033-08), and CURE.

Regulation of XIAP Translation and Induction by MDM2 following Irradiation

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Journal Title:

Cancer Cell

Volume:

Volume 15, Number 5

Publisher:

, Pages 363-375

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Increases in protein levels of XIAP in cancer cells have been associated with resistance to apoptosis induced by cellular stress. Herein we demonstrate that the upregulation of XIAP protein levels is regulated by MDM2 at the translational level. MDM2 was found to physically interact with the IRES of the XIAP 5′-UTR, and to positively regulate XIAP IRES activity. This XIAP IRES-dependent translation was significantly increased in MDM2-transfected cells where MDM2 accumulated in the cytoplasm. Cellular stress and DNA damage triggered by irradiation induced the dephosphorylation and cytoplasmic localization of MDM2, which also led to an increase in IRES-dependent XIAP translation. Upregulation of XIAP in MDM2-overexpressing cancer cells in response to irradiation resulted in resistance of these cells to radiation-induced apoptosis.Significance Overexpression of the MDM2 oncoprotein, which is often found in cancer cells, is associated with resistance to chemo-radiation therapy and poor prognosis of cancer patients. MDM2 is well characterized as an inhibitor of the tumor suppressor p53, and overexpression of MDM2 contributes to a growth advantage for cancer cells. However, the mechanism by which overexpression of MDM2 confers resistance to DNA damage induced by irradiation and chemotherapy are not fully elucidated. We report here that MDM2 was able to bind to XIAP mRNA and positively regulate the IRES-dependent XIAP translation during cellular stress triggered by irradiation. These results identify a p53-independent function for MDM2 in mediating XIAP translation, which is critical in effecting cancer cell response to chemo-radiation therapy.

Copyright information:

© 2009 Elsevier Inc.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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