title: Distinct functions of erythropoietin and stem cell factor are linked to activation of mTOR kinase signaling pathway in human erythroid progenitors.
abstract: Erythropoietin (EPO) and Stem Cell Factor (SCF) have partially distinct functions in erythroid cell development. The primary functions of EPO are to prevent apoptosis and promote differentiation, with a minor role as a mitogen. On the other hand SCF acts primarily as a mitogenic factor promoting erythroid cell proliferation with a minor role in inhibition of apoptosis. The concerted effects of these two growth factors are responsible for guiding initial commitment, expansion and differentiation of progenitors. The aim of the study was to identify signaling elements pertinent to translational control and elucidate whether both cytokines can contribute to protein translation providing some functional redundancy as seen with respect to apoptosis. The current study focused on non-apoptotic functions of SCF mediated through mTOR/p70S6 leading to protein translation and cell proliferation. We utilized a human primary erythroid progenitors and erythroblasts that are responsive to EPO and SCF to investigate the activation of mTOR/p70S6 kinases and their downstream effectors, the pathway primarily responsible for protein translation. We showed that mTOR, p70S6 kinases and their downstream signaling elements 4EBP1 and S6 ribosomal protein are all activated by SCF but not by EPO in primary erythroid progenitors. We also found that SCF is the sole contributor to activation of the protein translational machinery and activation of mTOR/p70S6 pathway is confined to the proliferative phase of erythroid differentiation program. Altogether these results demonstrate that unlike the survival function which is supported by both EPO and SCF protein translation essential for proliferation is governed by only SCF.
authors.affiliation: Department of Medicine and Biochemistry, University of Chicago, 5841 South Maryland Ave., Chicago, IL 60637, United States.
authors.forename: Renaud
authors.initials: R
authors.lastname: Geslain
authors.forename: Shahab
authors.initials: S
authors.lastname: Uddin
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Hongmei
authors.initials: H
authors.lastname: Jiang
authors.forename: Koen
authors.initials: K
authors.lastname: van Besien
authors.forename: Tao
authors.initials: T
authors.lastname: Pan
authors.forename: Amittha
authors.initials: A
authors.lastname: Wickrema
mesh_terms: D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D015672:Erythroid Precursor Cells / Q000378:metabolism*; D004921:Erythropoietin / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000378:metabolism / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*
chemical_list: D004921:Erythropoietin; D019869:Phosphatidylinositol 3-Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D019089:Stem Cell Factor; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human