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Mdmx promotes genomic instability independent of p53 and Mdm2

Oncogene volume 34, pages 846–856 (2015)Cite this article

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Abstract

The oncogene Mdmx is overexpressed in many human malignancies, and together with Mdm2, negatively regulates the p53 tumor suppressor. However, a p53-independent function of Mdmx that impacts genome stability has been described, but this function is not well understood. In the present study, we determined that of the 13 different cancer types evaluated, 6–90% of those that had elevated levels of Mdmx had concurrent inactivation (mutated or deleted) of p53. We show elevated levels of Mdmx-inhibited double-strand DNA break repair and induced chromosome and chromatid breaks independent of p53, leading to genome instability. Mdmx impaired early DNA damage-response signaling, such as phosphorylation of the serine/threonine-glutamine motif, mediated by the ATM kinase. Moreover, we identified Mdmx associated with Nbs1 of the Mre11-Rad50-Nbs1 (MRN) DNA repair complex, and this association increased upon DNA damage and was detected at chromatin. Elevated Mdmx levels also increased cellular transformation in a p53-independent manner. Unexpectedly, all Mdmx-mediated phenotypes also occurred in cells lacking Mdm2 and were independent of the Mdm2-binding domain (RING) of Mdmx. Therefore, Mdmx-mediated inhibition of the DNA damage response resulted in delayed DNA repair and increased genome instability and transformation independent of p53 and Mdm2. Our results reveal a novel p53- and Mdm2-independent oncogenic function of Mdmx that provides new insight into the many cancers that overexpress Mdmx.

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Acknowledgements

We thank Brandon Metge for technical expertise; Dr Jean-Christophe Marine for providing the Mdmx vector; Dr Stephen Jones for providing the Mdmx−/−p53−/− MEFs; members of the Eischen lab for thoughtful discussions and critical review of this manuscript. This work was supported by NCI grants F31CA150546 (AMC), T32CA009582 (AMC), R01CA117935 (CME) and R01CA160432 (CME), and NCI Cancer Center Support Grant P30CA068485 utilizing the Flow Cytometry Shared Resource.

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  1. Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA

    A M Carrillo, M P Arrate & C M Eischen

  2. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    A Bouska

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  1. A M Carrillo
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  2. A Bouska
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Correspondence to C M Eischen.

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Carrillo, A., Bouska, A., Arrate, M. et al. Mdmx promotes genomic instability independent of p53 and Mdm2. Oncogene 34, 846–856 (2015). https://doi.org/10.1038/onc.2014.27

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