Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity

Nomura, K. , Klejnot, M., Kowalczyk, D., Hock, A. K., Sibbet, G. J., Vousden, K. and Huang, D. T. (2017) Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity. Nature Structural and Molecular Biology, 24(7), pp. 578-587. (doi: 10.1038/nsmb.3414) (PMID:28553961)

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Abstract

MDM2–MDMX complexes bind the p53 tumor-suppressor protein, inhibiting p53's transcriptional activity and targeting p53 for proteasomal degradation. Inhibitors that disrupt binding between p53 and MDM2 efficiently activate a p53 response, but their use in the treatment of cancers that retain wild-type p53 may be limited by on-target toxicities due to p53 activation in normal tissue. Guided by a novel crystal structure of the MDM2–MDMX–E2(UbcH5B)–ubiquitin complex, we designed MDM2 mutants that prevent E2–ubiquitin binding without altering the RING-domain structure. These mutants lack MDM2's E3 activity but retain the ability to limit p53′s transcriptional activity and allow cell proliferation. Cells expressing these mutants respond more quickly to cellular stress than cells expressing wild-type MDM2, but basal p53 control is maintained. Targeting the MDM2 E3-ligase activity could therefore widen the therapeutic window of p53 activation in tumors.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Kowalczyk, Dominika and Huang, Professor Danny and Hock, Dr Andreas and Sibbet, Dr Gary and Klejnot, Ms Marta and Nomura, Koji and Vousden, Karen
Authors: Nomura, K., Klejnot, M., Kowalczyk, D., Hock, A. K., Sibbet, G. J., Vousden, K., and Huang, D. T.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Nature Structural and Molecular Biology
Publisher:Nature Publishing Group
ISSN:1545-9993
ISSN (Online):1545-9985
Published Online:29 May 2017
Copyright Holders:Copyright © 2017 Nature America, Inc., part of Springer Nature
First Published:First published in Nature Structural and Molecular Biology 24(7): 578-587
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher
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