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ASPP-MEDIATED DEPHOSPHORYLATION OF P53 BY PROTEIN PHOSPHATASE 1C

  • Author / Creator
    Millott, Robyn A
  • The Apoptotic Stimulating Proteins of p53 (ASPPs) are key regulators of the human tumour suppressor transcription factor, p53. These regulators either activate (ASPP1 and ASPP2) or inhibit (iASPP) p53’s function in response to DNA damage. iASPP is overexpressed and attributed to poor survival in several cancers including ovarian, lung, and prostate cancers, while ASPP2 is commonly downregulated in cancer. The molecular mechanisms by which the ASPP proteins mediate their opposing effects on p53 is currently not well understood. Phosphorylation of p53 has been well studied for its importance in p53 stability, localization, and transcriptional activity in response to DNA damage. Previous studies show the catalytic subunit of the Ser/Thr phosphatase, Protein Phosphatase 1 (PP1c), associates with the ASPP proteins, suggesting that ASPP proteins may mediate the post-translational dephosphorylation of p53. In this work, I have shown that the C-terminal Ankyrin and SH3 domains of iASPP and ASPP2 mediate dephosphorylation of p53Ser15 by PP1c. In addition, iASPP can mediate dephosphorylation of p53Thr18 and DYRK2 phosphorylated p53. Thus, I provide a potential mechanism by which the iASPP may modulate p53 function, and provide some insight into why the N-terminal truncations of ASPP2 may have apparent anti-apoptotic effects. In addition, we used iASPP-mediated dephosphorylation of p53 and mutagenesis of PP1cα and iASPP to provide validation of the newly elucidated iASPP:PP1c structure uncovered in the Glover Lab. In the process, I now hypothesize that the C-terminal tail of PP1c may move to accommodate ASPP-mediated dephosphorylation of p53. A better understanding of how ASPP proteins mediate their opposing functions on p53 may lead to more targeted therapies in cancer treatment.

  • Subjects / Keywords
  • Graduation date
    2017-11:Fall 2017
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/R3QF8JZ7F
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Master's
  • Department
    • Department of Biochemistry
  • Supervisor / co-supervisor and their department(s)
    • Glover, Mark (Biochemistry)
    • Holmes, Charles (Biochemistry)
  • Examining committee members and their departments
    • Weinfeld, Michael (Oncology)
    • Fahlman, Richard (Biochemistry)
    • Goping, Ing-Swie (Biochemistry)