title: Requirement for phosphatidylinositol 3'-kinase to protect hemopoietic progenitors against apoptosis depends upon the extracellular survival factor.
abstract: Hemopoietic growth factors promote survival of progenitor cells by preventing their apoptotic death. Recently, phosphatidylinositol 3'-kinase (PI 3-kinase) has been shown to be integral in the pathway by which insulin and nerve growth factor prevent apoptosis. In this work, we show that IL-3-dependent FDCP-1/Mac-1 murine hemopoietic progenitors express receptors for another growth factor, insulin-like growth factor-I (IGF-I), and that both IL-3 and IGF-I stimulate PI 3-kinase activity. We then demonstrate that IGF-I shares with IL-3 the properties of significantly promoting proliferation and enhancing survival of myeloid progenitor cells at concentrations as low as 3 ng/ml. IL-3 and IGF-I efficiently promote cell survival in the presence of inhibitors of either RNA synthesis (actinomycin D) or mitosis (mitomycin C), suggesting that both ligands promote survival by a process that is largely independent of RNA synthesis. To determine whether PI 3-kinase mediates IL-3- and IGF-I-induced inhibition of apoptosis, FDCP-1/Mac-1 cells were incubated with the PI 3-kinase inhibitor, wortmannin. While wortmannin inhibited both basal and IGF-I- and IL-3-induced PI 3-kinase enzyme activity, it did not affect the ability of IL-3 to protect FDCP-1/Mac-1 cells from apoptosis, even though it abrogated the IGF-I-induced inhibition of apoptosis. These data demonstrate that even though activation of PI 3-kinase is a pleiotropic feature of both IL-3 and IGF-I receptors in myeloid progenitors, prevention of apoptosis by IL-3 but not IGF-I is independent of PI 3-kinase. Survival of hemopoietic progenitors is therefore maintained by at least two different intracellular signaling pathways, one requiring PI 3-kinase and one that does not.
authors.affiliation: Department of Animal Sciences, University of Illinois, Urbana 61801, USA.
authors.forename: C
authors.initials: C
authors.lastname: Minshall
authors.forename: S
authors.initials: S
authors.lastname: Arkins
authors.forename: G G
authors.initials: GG
authors.lastname: Freund
authors.forename: K W
authors.initials: KW
authors.lastname: Kelley
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000633:toxicity; D005109:Extracellular Matrix / Q000187:drug effects / Q000201:enzymology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000201:enzymology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D016177:Macrophage-1 Antigen; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019869:Phosphatidylinositol 3-Kinases; D010716:Phosphatidylinositols / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis / Q000494:pharmacology*; D012313:RNA / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D007377:Interleukin-3; D016177:Macrophage-1 Antigen; D010716:Phosphatidylinositols; D012313:RNA; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor)