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Characterization of synthetic lethality between Mdm2 overexpression and genotoxic agents and identification of a novel function of the Mdmx oncogene in DNA repair

The oncogenes Mdm2 and Mdmx are often overexpressed in many human cancers. In addition to being negative regulators of the tumor suppressor p53, there is evidence these proteins have important p53-independent functions that are not clearly understood. Recently, a novel function of Mdm2 was identified where overexpression of Mdm2 inhibited double-strand DNA break repair through interacting with an important DNA repair protein, Nbs1, and this function of Mdm2 was independent of p53. Little was known about p53-independent functions of Mdmx and the contribution these functions may have on tumorigenesis. Here, I identify a novel interaction between Mdmx and Nbs1. Furthermore, I characterize a novel function of Mdmx that inhibits DNA damage response signaling and double-strand DNA break repair independent of both p53 and Mdm2. Specifically, Mdmx overexpression results in a decrease in the phosphorylation of the histone variant H2AX in addition to serine/glutamine or theronine/gluatamine motifs on substrates of the DNA-damage induced kinase ATM. Additionally, Mdmx overexpression promotes genome instability and confers transformation potential. Because increased levels of Mdm2 and Mdmx inhibit DNA break repair and promote genome instability, targeting this family of proteins pharmacologically has the potential to increase the efficacy of genotoxic drugs. Here, I demonstrate that the small molecule, Nutlin-3, causes an increase in Mdm2 protein levels, which results in an inhibition of double-strand DNA break repair and DNA damage response signaling independent of p53. In ovarian cancer cells with inactivated p53, Nutlin-3 combined with genotoxic agents, such as cisplatin, has a cooperative effect resulting in increased apoptosis. My results provide insight into generating novel treatment options for cancers with inactivated p53. Overall, my findings illustrate a conserved function of Mdm2 and Mdmx in the inhibition in double-strand DNA break repair. This function can be beneficial for developing novel therapeutic options for cancers with inactivated p53.

Identiferoai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-08142014-151931
Date15 August 2014
CreatorsCarrillo, Alexia Melo
ContributorsChristine Eischen, Amy Major, Mark Boothby, David Cortez, Katherine Friedman
PublisherVANDERBILT
Source SetsVanderbilt University Theses
LanguageEnglish
Detected LanguageEnglish
Typetext
Formatapplication/pdf
Sourcehttp://etd.library.vanderbilt.edu/available/etd-08142014-151931/
Rightsrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.

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