Mapping of EGFR treatment effects and uncovering DNA repair mechanisms using quantitative proteomics

    Research output: ThesisThesis fully internal (DIV)

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    Abstract

    In this thesis, we aimed to determine at the proteomic level how cancer cells deal with therapeutic targeting of cancer-inducing pathways or supporting non-cancerous pathways. To this end, we combined quantitative proteomics, the study of all proteins in cells, with a range of cell biological and genetic techniques to uncover mechanisms and markers of treatment efficacy. In these proteomics studies we made a number of discoveries.
    First off, we found that cells start to produce the protein Mucin-1 (MUC1) after they are treated with an inhibitor of EGFR, a growth factor receptor. We could also measure this increase in MUC1 in the blood plasma of tumor-bearing mice after they were treated with the EGFR inhibitor. We hope that in the future this can be used in cancer patients to determine if treatment with EGFR inhibitors is successful.
    In a second proteomics analysis we searched for proteins that would be degraded by the protein complex APC/C-Cdh1 after cells have finished dividing. Here we found that the protein CtIP, which is part of DNA repair processes, was degraded by the APC/C-Cdh1 after cell division, but also when DNA was damaged by irradiation.
    As a final result we found a new role of the protein Rif1. We found that this protein was required during cell divisions to process intertwined or non-replicated DNA. This processing is required to make sure that cell division are finished without damage to the DNA.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • van Vugt, Marcel, Supervisor
    • de Vries, Liesbeth, Supervisor
    • Medema, R. H., Assessment committee, External person
    • de Jong, Steven, Assessment committee
    • Kosterink, Jos, Assessment committee
    Award date13-Dec-2017
    Place of Publication[Groningen]
    Publisher
    Print ISBNs978-94-034-0298-7
    Electronic ISBNs978-94-034-0297-0
    Publication statusPublished - 2017

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