{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/83635"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/83635","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"The Role of Igf-1 and Il-4 in Myeloid Progenitor Cell Survival","abstract":"The development of myeloid progenitor cells requires paracrine growth factors to mediate the proliferation, differentiation and survival of these cells. In this thesis, we demonstrate that IGF-I and IL-4, a cytokine produced by activated T-lymphocytes, enhance the survival of CSF-stimulated progenitor cells. One particular enzyme activated by both IGF-I and IL-4 is phosphatidylinositol 3$\\sp\\prime$-kinase, a lipid kinase which phosphorylates phosphatidylinositol on its 3$\\sp\\prime$ carbon. We demonstrate that activation of this enzyme is critical for IGF-I- and IL-4-mediated inhibition of apoptosis in CSF-deprived myeloid progenitor cells. Although IL-3 effectively induces PI 3-kinase activity, this is not required for IL-3-stimulated survival of FDCP cells. These data suggest that at least two distinct pathways enhance the survival of myeloid cells, one that is dependent upon PI 3-kinase and one that involves another mechanism. We also clearly demonstrate that the downstream mediator of PI 3-kinase-stimulated survival in IGF-I- and IL-4-treated cells is the anti-apoptotic protein Bcl-2. In IL-3-deprived FDCP cells the levels of Bcl-2 decrease in a time-dependent fashion, and this is negatively correlated with an increase in the apoptotic population of these cells. Treatment of IL-3-deprived FDCP cells with IGF-I or IL-4 increases the expression of Bcl-2 protein relative to cells incubated in medium alone. This enhanced expression of Bcl-2 is dependent upon IGF-I- or IL-4-activated PI 3-kinase. Treatment of these cells with either wortmannin or LY294002, two potent inhibitors of PI 3-kinase activity, abrogates the ability of IGF-I or IL-4 to maintain the expression of Bcl-2 in FDCP cells. As expected neither inhibitor affected the ability of IL-3 to maintain Bcl-2 expression or inhibit apoptosis. These data confirm our initial findings which demonstrate that two distinct ligand-dependent mechanisms are involved in mediating the survival of myeloid progenitor cells. We also demonstrate that S6-kinase, an enzyme which mediates the downstream proliferative signal of PI 3-kinase, does not transduce IGF-I- or IL-4-stimulated inhibition of apoptosis. The expression of the pro-apoptotic protein, Bax, does not change even after IL-3 withdrawal for 24 h, and is not regulated by IL-3, IGF-I or IL-4 in the presence or absence of PI 3-kinase inhibitors. These data confirm previous studies that demonstrate cell survival is regulated by relative Bcl-2 and Bax ratios. Collectively, these data demonstrate that IGF-I and IL-4 enhance myeloid cell survival by increasing the expression of Bcl-2 via activation of PI 3-kinase, while IL-3 utilizes an alternative signaling pathway.","abstract_html":"The development of myeloid progenitor cells requires paracrine growth factors to mediate the proliferation, differentiation and survival of these cells. In this thesis, we demonstrate that IGF-I and IL-4, a cytokine produced by activated T-lymphocytes, enhance the survival of CSF-stimulated progenitor cells. One particular enzyme activated by both IGF-I and IL-4 is phosphatidylinositol 3$\\sp\\prime$-kinase, a lipid kinase which phosphorylates phosphatidylinositol on its 3$\\sp\\prime$ carbon. We demonstrate that activation of this enzyme is critical for IGF-I- and IL-4-mediated inhibition of apoptosis in CSF-deprived myeloid progenitor cells. Although IL-3 effectively induces PI 3-kinase activity, this is not required for IL-3-stimulated survival of FDCP cells. These data suggest that at least two distinct pathways enhance the survival of myeloid cells, one that is dependent upon PI 3-kinase and one that involves another mechanism. We also clearly demonstrate that the downstream mediator of PI 3-kinase-stimulated survival in IGF-I- and IL-4-treated cells is the anti-apoptotic protein Bcl-2. In IL-3-deprived FDCP cells the levels of Bcl-2 decrease in a time-dependent fashion, and this is negatively correlated with an increase in the apoptotic population of these cells. Treatment of IL-3-deprived FDCP cells with IGF-I or IL-4 increases the expression of Bcl-2 protein relative to cells incubated in medium alone. This enhanced expression of Bcl-2 is dependent upon IGF-I- or IL-4-activated PI 3-kinase. Treatment of these cells with either wortmannin or LY294002, two potent inhibitors of PI 3-kinase activity, abrogates the ability of IGF-I or IL-4 to maintain the expression of Bcl-2 in FDCP cells. As expected neither inhibitor affected the ability of IL-3 to maintain Bcl-2 expression or inhibit apoptosis. These data confirm our initial findings which demonstrate that two distinct ligand-dependent mechanisms are involved in mediating the survival of myeloid progenitor cells. We also demonstrate that S6-kinase, an enzyme which mediates the downstream proliferative signal of PI 3-kinase, does not transduce IGF-I- or IL-4-stimulated inhibition of apoptosis. The expression of the pro-apoptotic protein, Bax, does not change even after IL-3 withdrawal for 24 h, and is not regulated by IL-3, IGF-I or IL-4 in the presence or absence of PI 3-kinase inhibitors. These data confirm previous studies that demonstrate cell survival is regulated by relative Bcl-2 and Bax ratios. Collectively, these data demonstrate that IGF-I and IL-4 enhance myeloid cell survival by increasing the expression of Bcl-2 via activation of PI 3-kinase, while IL-3 utilizes an alternative signaling pathway.","abstract_has_math":true,"creators":["Minshall, Christian"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Animal Sciences","degree_department":null,"school":null,"contributors":["Kelley, Keith W."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2015,"date_issued":"2015-09-25T21:08:33Z","date_published":"2015-09-25T21:08:33Z","updated_at":"2026-07-22T22:26:21Z","subjects":["Biology, Cell"],"languages":["eng"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["(MiAaPQ)AAI9737202"],"render_values":[{"text":"(MiAaPQ)AAI9737202","href":null,"code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/2142/83635","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Kelley, Keith W."]},{"key":"dc:creator","label":"Author","values":["Minshall, Christian"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2015-09-25T21:08:33Z","10000-01-01","1997"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Animal Sciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Biology, Cell"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/83635","(MiAaPQ)AAI9737202"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["The development of myeloid progenitor cells requires paracrine growth factors to mediate the proliferation, differentiation and survival of these cells. In this thesis, we demonstrate that IGF-I and IL-4, a cytokine produced by activated T-lymphocytes, enhance the survival of CSF-stimulated progenitor cells. One particular enzyme activated by both IGF-I and IL-4 is phosphatidylinositol 3$\\sp\\prime$-kinase, a lipid kinase which phosphorylates phosphatidylinositol on its 3$\\sp\\prime$ carbon. We demonstrate that activation of this enzyme is critical for IGF-I- and IL-4-mediated inhibition of apoptosis in CSF-deprived myeloid progenitor cells. Although IL-3 effectively induces PI 3-kinase activity, this is not required for IL-3-stimulated survival of FDCP cells. These data suggest that at least two distinct pathways enhance the survival of myeloid cells, one that is dependent upon PI 3-kinase and one that involves another mechanism. We also clearly demonstrate that the downstream mediator of PI 3-kinase-stimulated survival in IGF-I- and IL-4-treated cells is the anti-apoptotic protein Bcl-2. In IL-3-deprived FDCP cells the levels of Bcl-2 decrease in a time-dependent fashion, and this is negatively correlated with an increase in the apoptotic population of these cells. Treatment of IL-3-deprived FDCP cells with IGF-I or IL-4 increases the expression of Bcl-2 protein relative to cells incubated in medium alone. This enhanced expression of Bcl-2 is dependent upon IGF-I- or IL-4-activated PI 3-kinase. Treatment of these cells with either wortmannin or LY294002, two potent inhibitors of PI 3-kinase activity, abrogates the ability of IGF-I or IL-4 to maintain the expression of Bcl-2 in FDCP cells. As expected neither inhibitor affected the ability of IL-3 to maintain Bcl-2 expression or inhibit apoptosis. These data confirm our initial findings which demonstrate that two distinct ligand-dependent mechanisms are involved in mediating the survival of myeloid progenitor cells. We also demonstrate that S6-kinase, an enzyme which mediates the downstream proliferative signal of PI 3-kinase, does not transduce IGF-I- or IL-4-stimulated inhibition of apoptosis. The expression of the pro-apoptotic protein, Bax, does not change even after IL-3 withdrawal for 24 h, and is not regulated by IL-3, IGF-I or IL-4 in the presence or absence of PI 3-kinase inhibitors. These data confirm previous studies that demonstrate cell survival is regulated by relative Bcl-2 and Bax ratios. Collectively, these data demonstrate that IGF-I and IL-4 enhance myeloid cell survival by increasing the expression of Bcl-2 via activation of PI 3-kinase, while IL-3 utilizes an alternative signaling pathway.","Made available in DSpace on 2015-09-25T21:08:33Z (GMT). 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In this thesis, we demonstrate that IGF-I and IL-4, a cytokine produced by activated T-lymphocytes, enhance the survival of CSF-stimulated progenitor cells. One particular enzyme activated by both IGF-I and IL-4 is phosphatidylinositol 3$\\sp\\prime$-kinase, a lipid kinase which phosphorylates phosphatidylinositol on its 3$\\sp\\prime$ carbon. We demonstrate that activation of this enzyme is critical for IGF-I- and IL-4-mediated inhibition of apoptosis in CSF-deprived myeloid progenitor cells. Although IL-3 effectively induces PI 3-kinase activity, this is not required for IL-3-stimulated survival of FDCP cells. These data suggest that at least two distinct pathways enhance the survival of myeloid cells, one that is dependent upon PI 3-kinase and one that involves another mechanism. We also clearly demonstrate that the downstream mediator of PI 3-kinase-stimulated survival in IGF-I- and IL-4-treated cells is the anti-apoptotic protein Bcl-2. In IL-3-deprived FDCP cells the levels of Bcl-2 decrease in a time-dependent fashion, and this is negatively correlated with an increase in the apoptotic population of these cells. Treatment of IL-3-deprived FDCP cells with IGF-I or IL-4 increases the expression of Bcl-2 protein relative to cells incubated in medium alone. This enhanced expression of Bcl-2 is dependent upon IGF-I- or IL-4-activated PI 3-kinase. Treatment of these cells with either wortmannin or LY294002, two potent inhibitors of PI 3-kinase activity, abrogates the ability of IGF-I or IL-4 to maintain the expression of Bcl-2 in FDCP cells. As expected neither inhibitor affected the ability of IL-3 to maintain Bcl-2 expression or inhibit apoptosis. These data confirm our initial findings which demonstrate that two distinct ligand-dependent mechanisms are involved in mediating the survival of myeloid progenitor cells. We also demonstrate that S6-kinase, an enzyme which mediates the downstream proliferative signal of PI 3-kinase, does not transduce IGF-I- or IL-4-stimulated inhibition of apoptosis. The expression of the pro-apoptotic protein, Bax, does not change even after IL-3 withdrawal for 24 h, and is not regulated by IL-3, IGF-I or IL-4 in the presence or absence of PI 3-kinase inhibitors. These data confirm previous studies that demonstrate cell survival is regulated by relative Bcl-2 and Bax ratios. Collectively, these data demonstrate that IGF-I and IL-4 enhance myeloid cell survival by increasing the expression of Bcl-2 via activation of PI 3-kinase, while IL-3 utilizes an alternative signaling pathway.","Made available in DSpace on 2015-09-25T21:08:33Z (GMT). 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