Effects of chimeric and modified cytokines and p13k/akt inhibition on apoptosis and proliferation of human hematopoietic cells / by Oussama A. Saleh.
| Author/creator | Saleh, Oussama A. author. |
| Other author | McCubrey, James A., degree supervisor. |
| Other author | East Carolina University. Department of Biology. |
| Format | Theses and dissertations |
| Production | 2001. |
| Description | i, 105 leaves : illustrations ; 28 cm |
| Supplemental Content | Access via ScholarShip |
| Subjects |
| Summary | Repopulating hematopoietic cell compartments after myeloablative chemotherapy remains a key objective in a successful chemotherapy program. Modified and chimeric cytokines have been developed to help reduce inflammation, fever and hospitalization time for patients. Some of these cytokines are daniplestim, myelopoietin-1 and progenipoietin-1 (ProGp-1). The IL-3 receptor agonist, daniplestim, binds to the IL-3 receptor-a subunit with 60-fold greater affinity and induces cell proliferation and colony forming unit formation 10 to 22-fold better than native IL-3. The chimeric cytokine myelopoietin-1 is composed of daniplestim and a G-CSF receptor agonists it binds both the IL-3 and G-CSF receptors. ProGp-1, another chimera, is composed of G-CSF and FL receptor agonists it binds both the G-CSF receptor and FLT-3. The purpose of this study was to investigate the effects of daniplestim, myelopoietin-1 and ProGP-1 on prevention of apoptosis in the human hematopoietic cell line OCI-AML.5. Daniplestim, myelopoietin-1 and ProGP-1 promoted cellular proliferation better than native IL-3, G CSF or FL separately but stimulated proliferation similar to their co-addition. Daniplestim, myelopoietin-1 and ProGP-1 prevented apoptosis to a greater degree than native IL-3, G-CSF or FL. They promoted maintenance of the mitochondrial membrane potential better than the native separate cytokines. The chimeras also promoted a lower redox potential as higher levels of free radicals were detected after cytokine treatment than in C3^okine-deprived cells implying increased respiration. These experiments indicate that daniplestim, myelopoietin-1 and ProGP-1 promote proliferation and prevent apoptosis of human hematopoietic cells better than the native cytokines making them ideal for repopulating the hematopoietic precursor cell compartments after chemotherapy. Inhibiting the PI3K/AKT pathway caused the cells to stop proliferating, suppressed the expression of key genes and transcription factors and induced apoptosis within 48 hrs. These results show the more centralized role of the PDK/Akt pathway in cellular proliferation and prevention of apoptosis in hematopoietic cells. |
| General note | Presented to the faculty of the Department of Biology. |
| General note | Advisor: James A. McCubrey |
| Dissertation note | M.S. East Carolina University 2001 |
| Bibliography note | Includes bibliographical references (leaves 97-105). |
| Genre/form | Academic theses. |
| Genre/form | Academic theses. |
| Genre/form | Thèses et écrits académiques. |
Availability
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|---|---|---|---|---|
| Joyner | University Archives | ASK AT SPECIAL COLLECTIONS DESK | ✔ Available | Request Material |
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