title: Interleukin-3-stimulated haemopoietic stem cell proliferation. Evidence for activation of protein kinase C and Na+/H+ exchange without inositol lipid hydrolysis.
abstract: Interleukin 3 (IL-3) is an important regulator of haemopoietic stem cell proliferation both in vivo and in vitro. Little is known about the possible mechanisms whereby this growth factor acts on stem cells to stimulate cell survival and proliferation. Here we have investigated the role of intracellular pH and the Na+/H+ antiport in stem cell proliferation using the multipotential IL-3-dependent stem cell line, FDCP-Mix 1. Evidence is presented that IL-3 can stimulate the activation of an amiloride-sensitive Na+/H+ exchange via protein kinase C activation. IL-3-mediated activation of the Na+/H+ exchange is not observed in FDCP-Mix 1 cells where protein kinase C levels have been down-modulated by treatment with phorbol esters. Also the protein kinase C inhibitor H7 can inhibit IL-3-mediated increases in intracellular pH. This activation of Na+/H+ exchange via protein kinase C has been shown to occur with no measurable effects of IL-3 on inositol lipid hydrolysis or on cytosolic Ca2+ levels. Evidence is also presented that this IL-3-stimulated alkalinization acts as a signal for cellular proliferation in stem cells.
authors.affiliation: Department of Biochemistry and Applied Molecular Biology, University of Manchester Institute of Science and Technology, U.K.
authors.forename: A D
authors.initials: AD
authors.lastname: Whetton
authors.forename: S J
authors.initials: SJ
authors.lastname: Vallance
authors.forename: P N
authors.initials: PN
authors.lastname: Monk
authors.forename: E J
authors.initials: EJ
authors.lastname: Cragoe
authors.forename: T M
authors.initials: TM
authors.lastname: Dexter
authors.forename: C M
authors.initials: CM
authors.lastname: Heyworth
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004789:Enzyme Activation; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D007295:Inositol Phosphates / Q000378:metabolism; D007377:Interleukin-3 / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism
chemical_list: D007295:Inositol Phosphates; D007377:Interleukin-3; D007546:Isoquinolines; D010879:Piperazines; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D013936:Thymidine