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The Disruption of iASPP Binding to PP-1cα via Small Molecules Sourced from Marine Organisms Open Access

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Other title
Subject/Keyword
Small Molecules
Protein-Protein Disruption
PP-1cα
Marine Organisms
Disruption of iASPP to PP-1cα
iASPP
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
McLellan, Melissa M.
Supervisor and department
Holmes, Charles (Biochemistry)
Examining committee member and department
Posse de Chaves, Elena (Pharmacology)
Fahlman, Richard (Biochemistry)
Fliegel, Larry (Biochemistry)
Department
Department of Biochemistry
Specialization

Date accepted
2017-09-12T14:36:44Z
Graduation date
2017-11:Fall 2017
Degree
Master of Science
Degree level
Master's
Abstract
Protein Phosphatase-1 (PP-1c) is a broad specificity Ser/Thr phosphatase catalytic subunit responsible for a variety protein dephosphorylation events in eukaryotic cells. The specificity and activity of PP-1c is largely controlled by over 200 regulatory subunits, including the Apoptotic Stimulating Proteins of p53 (ASPP). ASPP1 and ASPP2 are two members of the ASPP family that are responsible for promoting the pro-apoptotic activity of the tumour suppressor p53, while an inhibitory ASPP (termed iASPP) is responsible for inhibiting p53 activity. PP-1c, iASPP, and p53 form a protein complex which promotes the dephosphorylation of p53, and in turn, inhibits its pro-apoptotic activity. iASPP is over-expressed in two thirds of all human cancers containing wild-type p53. The purpose of this Masters thesis project was to identify small molecules that may disrupt iASPP•PP-1c binding as a necessary first step to hindering dephosphorylation of p53 by PP-1c. The principal hypothesis was that the iASPP•PP-1c protein complex could be targeted for disruption with bioactive marine compounds. Such compounds may have the potential to be novel anti-cancer drugs in cancer types that over-express iASPP. This project was determined to be feasible because preliminary data by Dr. Tamara Arnold demonstrated that two marine compounds, Sokotrasterol Sulfate and Suvanine, disrupt iASPP•PP-1cα binding. The results of this thesis show that iASPP•PP-1c binding can be targeted for disruption. Through the use of a novel protein-protein binding assay, I identified two novel iASPP disruptors, called Halistanol Sulfate and Coscinamide B. The potency and specificity of Halistanol Sulfate, Sokotrasterol Sulfate, and Suvanine were further characterized and all three demonstrated specificity towards the ASPP family vs. other PP-1c regulatory subunits, such as TIMAP (TGF-β-Inhibited Membrane-Associated Protein). Additionally, Suvanine preferentially disrupted iASPP binding to PP-1cα vs. ASPP2; therefore, Suvanine is the most promising candidate for specific iASPP•PP-1c disruption. Finally, during this investigation for PP-1c disruptors, I was also able to identify marine compounds that inhibit PP-1c activity. I discovered an abundant new source of the small molecule, Motuporin, as well, I discovered a novel bromophenol compound that potently inhibits the activity of PP-1c.
Language
English
DOI
doi:10.7939/R3P55DW9N
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.
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