ERA

Download the full-sized PDF of ASPP-MEDIATED DEPHOSPHORYLATION OF P53 BY PROTEIN PHOSPHATASE 1CDownload the full-sized PDF

Analytics

Share

Permanent link (DOI): https://doi.org/10.7939/R3QF8JZ7F

Download

Export to: EndNote  |  Zotero  |  Mendeley

Communities

This file is in the following communities:

Graduate Studies and Research, Faculty of

Collections

This file is in the following collections:

Theses and Dissertations

ASPP-MEDIATED DEPHOSPHORYLATION OF P53 BY PROTEIN PHOSPHATASE 1C Open Access

Descriptions

Other title
Subject/Keyword
Apoptotic Stimulating Proteins of p53
Protein Phosphatase 1
p53 phosphorylation
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Millott, Robyn A
Supervisor and department
Holmes, Charles (Biochemistry)
Glover, Mark (Biochemistry)
Examining committee member and department
Goping, Ing-Swie (Biochemistry)
Fahlman, Richard (Biochemistry)
Weinfeld, Michael (Oncology)
Department
Department of Biochemistry
Specialization

Date accepted
2017-08-18T11:57:04Z
Graduation date
2017-11:Fall 2017
Degree
Master of Science
Degree level
Master's
Abstract
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.
Language
English
DOI
doi:10.7939/R3QF8JZ7F
Rights
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. 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.
Citation for previous publication

File Details

Date Uploaded
Date Modified
2017-08-18T17:57:04.634+00:00
Audit Status
Audits have not yet been run on this file.
Characterization
File format: pdf (PDF/A)
Mime type: application/pdf
File size: 9389946
Last modified: 2017:11:08 17:36:40-07:00
Filename: Millott_Robyn_A_201708_MSc.pdf
Original checksum: a7c9e259e7702ffee29839a845f55e06
Activity of users you follow
User Activity Date