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dc.contributor.advisorBall, Kathrynen
dc.contributor.advisorElfick, Alistairen
dc.contributor.authorGil Mir, Maria Eugeniaen
dc.date.accessioned2017-12-18T12:26:53Z
dc.date.available2017-12-18T12:26:53Z
dc.date.issued2016-11-29
dc.identifier.urihttp://hdl.handle.net/1842/25781
dc.description.abstractp53 is a key component of the protein network that regulates cell cycle progression and prevents cancer. Under non-stressed conditions, its activity is controlled by an autoregulatory feedback loop with MDM2 that maintains low levels of the p53 protein. However, in response to stress signals, p53 is triggered to become active. MDM2 has been reported to regulate p53 by a combination of mechanisms: ubiquitination using its E3-ligase capability, chaperone activity in an ATP-dependent manner and directly transrepressing p53. Because of MDM2's central role in the control of p53, it has been the target of intense drug development efforts. A family of small molecules, the Nutlins, can bind to an MDM2 pocket modulating the p53: MDM2 complex. This leads to p53 activation and growth inhibitory effects. The aim of our study was to analyse the interactome of endogenous MDM2 and to determine whether anti-cancer drugs, such as Nutlin-3, could stabilise or disrupt sets of MDM2 interactions in order to better understand the p53- dependent and independent functions of MDM2 as a signalling hub, as well as the p53-independent activity of Nutlin-3. Results show a remarkable difference in the sets of proteins found in MDM2 complexes in control and Nutlin-3 treated cells. Two proteins, TRIM25 and OTUB2, were selected from the output list for validation based on their known functions in the ubiquitin signalling network. Binding has been studied in detail and confirmed using both in cell and in vitro techniques. The data highlight potentially novel functions for MDM2 and provides insight into the on-target p53-independent activities of Nutlin-3. Additionally, and with the aim of blocking p53 ubiquitination by MDM2, I have developed probes that are able to inhibit the ubiquitylation of p53 in vitro.en
dc.contributor.sponsorotheren
dc.language.isoen
dc.publisherThe University of Edinburghen
dc.subjectMDM2en
dc.subjectinteractomeen
dc.subjectubiquitinationen
dc.subjectp53en
dc.subjectOTUB2en
dc.subjectTRIM25en
dc.titleExpanding the MDM2 interactomeen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.rights.embargodate2100-12-31
dcterms.accessRightsRestricted Accessen


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