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You searched for +publisher:"University of North Carolina" +contributor:("Okumu, Denis"). One record found.

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University of North Carolina

1. Okumu, Denis. Lyn regulates drug resistance mechanisms in chronic myelogenous leukemia (CML).

Degree: Pharmacology, 2018, University of North Carolina

Acquired resistance to anti-cancer therapy presents a critical challenge to effective clinical management of chronic myelogenous leukemia (CML). Drug-resistant CML cells devise diverse molecular adaptations to evade therapy. Examples of such adaptations include: target (Bcr-Abl) mutations that eliminate drug binding, target amplification, up-regulation of drug exporter proteins, and activation of alternative kinase(s). The CML cell (Myl-R) model described in this dissertation is a classic example of how CML cells can activate alternative kinase(s) to promote cell survival. Herein, I discuss two molecular adaptations regulated by Lyn in Myl-R cells. In the first project, I showed that increased Lyn expression and activity in Myl-R cells up-regulated the expression and stability of BIRC6, a member of the inhibitor of apoptosis proteins (IAP) family known to bind and inactivate active caspases. BIRC6’s role in promoting imatinib resistance was confirmed by the 15-fold increase in imatinib sensitivity upon BIRC6 shRNA knockdown. Pharmacological or genetic inhibition of Lyn reduced BIRC6 expression and stability. Further, BIRC6 stability was increased via Lyn-dependent phosphorylation of serine residues in a region that overlapped with caspase cleavage motifs. Pharmacological inhibition of Lyn resulted in caspase-mediated degradation of BIRC6. In the second project, I am investigating Lyn’s role in regulating creatine uptake by Myl-R cells. Our lab previously showed that total intracellular creatine pool was 5-fold higher in Myl-R than Myl cells. Our unpublished data show that the increased intracellular creatine comes from uptake from the cell culture media and not de novo synthesis. I, therefore, investigated the role of creatine in Myl-R cells by incubating the cells in normal growth media into which competitive inhibitors of creatine uptake were added. Our data show that reduction in total intracellular creatine pool lowered cell viability. Others previously showed that the Na+/K+-ATPase pump activity was critical for creatine uptake. Our data show that Lyn inhibition or shRNA knockdown reduced Na+/K+-ATPase activity and total intracellular creatine pool, suggesting a tripartite signaling cascade that supports Myl-R cell survival. Taken together, these studies enrich our understanding of the diverse therapy-survival mechanisms utilized by CML cells, and provide insights into novel targets for effective cure of CML. Advisors/Committee Members: Okumu, Denis, Graves, Lee, Johnson, Gary, Yeh, Jen Jen, Zhang, Yanping, Baines, Antonio, University of North Carolina at Chapel Hill.

Subjects/Keywords: School of Medicine; Department of Pharmacology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Okumu, D. (2018). Lyn regulates drug resistance mechanisms in chronic myelogenous leukemia (CML). (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:070f858a-ab62-46b2-bec6-bf6e771fc340

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Okumu, Denis. “Lyn regulates drug resistance mechanisms in chronic myelogenous leukemia (CML).” 2018. Thesis, University of North Carolina. Accessed October 30, 2020. https://cdr.lib.unc.edu/record/uuid:070f858a-ab62-46b2-bec6-bf6e771fc340.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Okumu, Denis. “Lyn regulates drug resistance mechanisms in chronic myelogenous leukemia (CML).” 2018. Web. 30 Oct 2020.

Vancouver:

Okumu D. Lyn regulates drug resistance mechanisms in chronic myelogenous leukemia (CML). [Internet] [Thesis]. University of North Carolina; 2018. [cited 2020 Oct 30]. Available from: https://cdr.lib.unc.edu/record/uuid:070f858a-ab62-46b2-bec6-bf6e771fc340.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Okumu D. Lyn regulates drug resistance mechanisms in chronic myelogenous leukemia (CML). [Thesis]. University of North Carolina; 2018. Available from: https://cdr.lib.unc.edu/record/uuid:070f858a-ab62-46b2-bec6-bf6e771fc340

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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