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Permanent link (DOI): https://doi.org/10.7939/R3CF9JD3M

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From the basic understanding of N-myristoylation during apoptosis to a potential personalized medical treatment of B cell lymphomas Open Access

Descriptions

Other title
Subject/Keyword
Myristoylation
Burkitt lymphoma
N-myristoyltransferase
Apoptosis
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Perinpanayagam, Conganige M.
Supervisor and department
Berthiaume, Luc (Cell Biology)
Examining committee member and department
Bouvier, Michel (Biochemistry)
Baksh, Shairaz (Pediatrics)
Eitzen, Gary (Cell Biology)
Simmen, Thomas (Cell Biology)
Department
Department of Cell Biology
Specialization

Date accepted
2013-09-26T11:07:56Z
Graduation date
2013-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Myristoylation is a type of fatty acylation that involves the irreversible attachment of myristate (C14) to an amino-terminal glycine of a protein via an amide bond by N-myristoyltransferase (NMT). The two human N-myristoyltransferases (NMT1 and NMT2) typically play a pro-survival role in cells and their expression levels are increased in various cancers. Myristoylation occurs both co-translationally during protein synthesis and post-translationally during apoptosis. Our laboratory and others have identified several caspase-cleaved post-translationally myristoylated proteins during apoptosis and demonstrated the existence of numerous others. Hence, we hypothesized that myristoylation plays critical roles in both the survival and death of the cell by regulating apoptosis. Therefore, we were compelled to investigate the regulation of NMTs during apoptosis. Herein, we demonstrate an elegant interplay between caspases and NMTs during apoptosis whereby caspases not only cleave substrates for post-translational myristoylation but also the NMTs themselves. Caspase-3 and -8 cleave NMT1 while only caspase-3 cleaves NMT2. Interestingly, the cleavages of NMTs did not abrogate their activity, actually caspase-cleavage increased NMT2 activity while that of NMT1 remained unchanged. Furthermore, the cleavages of the N-termini of both enzymes removed electrostatically charged domains resulting in a change of subcellular localization, potentially affecting NMTs’ substrate specificities as the cell switches from co- to post-translational myristoylation. Our data and those of others suggest that NMTs are emerging as novel regulators of apoptosis. Because the regulation of the apoptotic process is usually defective in cancer cells, we further hypothesized that the regulation of the co- and post-translational myristoylation processes could also be defective in cancer cells. Our search for potential myristoylation “abnormalities” in cancer cells surprisingly revealed that NMT2 levels were down-regulated in Burkitt lymphomas, indicating that NMT2 could also play a pro-apoptotic role in hematologic cancers. We then exploited this unique molecular context by using low concentrations of a highly selective NMT inhibitor to preferentially kill malignant Burkitt lymphoma cells that only express one NMT (NMT1) and spare “normal” immortalized B lymphocytes that have both NMTs. This synthetically lethal approach could represent a novel personalized medical treatment option with minimized side-effects for lymphomas and perhaps other cancers devoid of NMT2.
Language
English
DOI
doi:10.7939/R3CF9JD3M
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Perinpanayagam, M.A., Beauchamp, E., Martin, D.D.O., Sim, J.Y.W., Yap, M.C., Berthiaume, L.G. The regulation of co- and post-translational myristoylation of proteins during apoptosis: interplay of N-myristoyltransferases and caspases. FASEB J. (2013) 27(2), 811-21

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