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dc.contributor.supervisor Dodd, Janice (Physiology) [Advisor]; Gibson, Spencer (Biochemistry and Medical Genetics) [Co-advisor] en
dc.contributor.author Panigrahi, Soumya
dc.date.accessioned 2009-09-03T14:34:23Z
dc.date.available 2009-09-03T14:34:23Z
dc.date.issued 2009-09-03T14:34:23Z
dc.identifier.uri http://hdl.handle.net/1993/3188
dc.description.abstract The non-receptor tyrosine kinase activity of fusion gene BCR-ABL derived oncoproteins is the key factor responsible for development and progress of Philadelphia positive (Ph+) chronic myeloid leukemia (CML). In the search for a superior and novel peptide-based inhibitor of Bcr-Abl, here I investigated a naturally occurring molecule, called apoptin. Apoptin is a 13.6 kDa protein derived from chicken anemia virus (CAV) and known to induce apoptosis in a wide range of transformed but not in primary cells. Apoptin is a protein without any reported structural and/or functional homolog and is an interesting candidate to initiate protein-protein interactions and subsequent downstream effects. Initially by an array-based analysis I found that apoptin interacts with the SH3 domain of Abl. By high stringency pull-down and co-immunoprecipitation assays the apoptin and Bcr-Abl interaction was further confirmed. Subsequently, a set of apoptin and Bcr-Abl deletion mutants were used to map this interaction precisely that mainly occurred between a proline rich domain of apoptin and the SH3 domain of Bcr-Abl. I further investigated the role of apoptin on Bcr-Abl. Apoptin was able to modify the phosphorylation of a series of targets (e.g. CrkL, STAT5, c-Myc) downstream of Bcr-Abl kinase. In addition, I used computational algorhythms for protein modeling to study the 3D structure of apoptin and it’s docking with Bcr-Abl at the molecular level. In controlled studies using the 2-pheny-laminopyrimidine derived specific tyrosine kinase inhibitor Imatinib® I found that apoptin has comparable effects on CML cells, suggesting that the interacting segment of the apoptin molecule acts as an adaptor and negatively regulates the Bcr-Abl kinase by deactivating many cell proliferation and anti-apoptotic pathways in CML cells. Briefly, this work provides important insights towards the development of peptide based tyrosine kinase inhibitors as new anti-cancer agents. en
dc.format.extent 4867993 bytes
dc.format.mimetype application/pdf
dc.language.iso en_US
dc.rights info:eu-repo/semantics/openAccess
dc.subject Apoptin en
dc.subject tyrosine-kinase-inhibitor en
dc.title APOPTIN AND ITS DERIVATIVES AS MOLECULAR CLUES TOWARDS THE DEVELOPMENT OF NOVEL TYROSINE KINASE INHIBITORS en
dc.type info:eu-repo/semantics/doctoralThesis
dc.degree.discipline Physiology en
dc.contributor.examiningcommittee Shiu, Robert (Physiology)[Internal Examiner]; Wrogemann, Klaus (Biochemistry and Medical Genetics)[Internal Examiner]; Foley, Ronan (McMaster University, Pathology and Molecular Medicine, Canada)[External Examiner] en
dc.degree.level Doctor of Philosophy (Ph.D.) en
dc.description.note October 2008 en


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