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    Mdm2-p53 Signaling in Tissue Homeostasis and the DNA Damage Response: A Dissertation

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    Authors
    Gannon, Hugh S.
    Faculty Advisor
    Hong Zhang, Ph.D.
    Academic Program
    Cell Biology
    UMass Chan Affiliations
    Molecular, Cell and Cancer Biology
    Document Type
    Doctoral Dissertation
    Publication Date
    2012-06-28
    Keywords
    Proto-Oncogene Proteins c-mdm2
    Tumor Suppressor Protein p53
    Homeostasis
    DNA Damage
    Cell Transformation
    Neoplastic
    Amino Acids, Peptides, and Proteins
    Animal Experimentation and Research
    Cancer Biology
    Cell and Developmental Biology
    Cells
    Genetic Phenomena
    Neoplasms
    Tissues
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    Abstract
    The p53 transcription factor responds to various cellular stressors by regulating the expression of numerous target genes involved in cellular processes such as cell cycle arrest, apoptosis, and senescence. As these downstream pathways are harmful to the growth and development of normal cells when prolonged or deregulated, p53 activity needs to be under tight regulatory control. The Mdm2 oncoprotein is the chief negative regulator of p53, and many mouse models have demonstrated that absence of Mdm2 expression leads to constitutive p53 activation in a variety of cell types. While unregulated p53 can be deleterious to cells, functional p53 is essential for tumor suppression, as many human cancers harbor p53 mutations and p53 knockout mice rapidly develop spontaneous tumors. Therefore, the mechanisms that control p53 regulation by Mdm2 are critical to ensure p53 activity in the appropriate cellular context. Many genetically engineered mouse models have been created to analyze p53 and Mdm2 functions and these studies have yielded valuable insights into their physiological roles. This dissertation will describe the generation and characterization of novel mutant Mdm2 mouse models and their use to interrogate the roles of p53-Mdm2 signaling in tissue homeostasis and cell stress responses. Deletion of Mdm2 in epidermal progenitor cells of the skin and hair follicles resulted in progressive hair loss and decreased skin integrity, phenotypes that are characteristic of premature aging. Furthermore, p53 protein levels, p53 target gene expression, and cellular senescence were all upregulated in the skins of these mice, and epidermal stem cell numbers and function were diminished. These results indicate that Mdm2 is necessary to limit p53 activity in adult tissues to ensure normal stem cell function. Additional mouse models used to determine the role of Mdm2 phosphorylation will also be presented. DNA damage triggers an extensive cellular response, including activation of the ATM kinase. ATM activity is necessary for p53 protein stabilization and, therefore, p53 activation, but in vivo evidence suggests that phosphorylation of p53 itself had little effect on p53 stability. ATM was previously shown to phosphorylate MDM2 at serine residue 395 (394 in mice), and we generated knock-in mutant mouse models to study the role of this posttranslational modification in vivo. Absence of this phosphorylation site led to greatly diminished p53 stability and function in response to γ-irradiation and increased spontaneous tumorigenesis in mice. Conversely, a phosphomimic model demonstrated prolonged p53 activation in cells treated with γ-irradiation, which revealed that phosphorylation of this Mdm2 residue controls the duration of the DNA damage response. Therefore, these mouse models have uncovered new roles for the p53-Mdm2 regulatory axis in vivo and will be useful reagents in future studies of posttranslational modifications in oncogene and DNA damage-induced tumorigenesis.
    DOI
    10.13028/sfjc-xh51
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/31981
    Notes

    This dissertation received the 2012 Dean's Award for Most Insightful Doctoral Thesis Research from the Graduate School of Biomedical Sciences at the University of Massachusetts Medical School.

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    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/sfjc-xh51
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