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

  • Author / Creator
    Perinpanayagam, Conganige M.
  • 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.

  • Subjects / Keywords
  • Graduation date
    Fall 2013
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • 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
  • Institution
    University of Alberta
  • Degree level
  • Department
  • Supervisor / co-supervisor and their department(s)
  • Examining committee members and their departments
    • Bouvier, Michel (Biochemistry)
    • Baksh, Shairaz (Pediatrics)
    • Eitzen, Gary (Cell Biology)
    • Simmen, Thomas (Cell Biology)