title: Hematopoietic growth factors signal through the formation of reactive oxygen species.
abstract: Hematopoietic growth factors (HGFs) stimulate growth, differentiation, and prevent apoptosis of progenitor cells. Each growth factor has a specific cell surface receptor, which activates both unique and shared signal transduction pathways. We found that several HGFs, including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), steel factor (SF), and thrombopoietin (TPO) induce a rapid increase in reactive oxygen species (ROS) in quiescent cells. In an effort to understand the potential biochemical and biological consequences of increased ROS in these cells, we exposed growth factor-deprived cells to hydrogen peroxide (H2O2) at concentrations that increased intracellular ROS. H2O2 induced a dose-dependent increase in tyrosine phosphorylation, including increased tyrosine phosphorylation of the GM-CSF receptor beta chain (betac), STAT5, and other signaling proteins. H2O2 also induced expression of the early response gene c-FOS, and G1- to S-phase transition, but not S- to G2/M-phase transition of MO7e cells. The cell permeable antioxidant pyrrolidine dithiocarbamate (PDTC) decreased the intracellular levels of ROS and inhibited tyrosine phosphorylation induced by GM-CSF in MO7e cells, suggesting that ROS generation plays an important role in GM-CSF signaling. Consistent with this notion, PDTC and two other antioxidants, N-acetyl cysteine and 2-mercaptoethanol, reduced growth and viability of MO7e cells. These results suggest that generation of ROS in response to HGFs may contribute to downstream signaling events, especially those involving tyrosine phosphorylation.
authors.affiliation: Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sattler
authors.forename: T
authors.initials: T
authors.lastname: Winkler
authors.forename: S
authors.initials: S
authors.lastname: Verma
authors.forename: C H
authors.initials: CH
authors.lastname: Byrne
authors.forename: G
authors.initials: G
authors.lastname: Shrikhande
authors.forename: R
authors.initials: R
authors.lastname: Salgia
authors.forename: J D
authors.initials: JD
authors.lastname: Griffin
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D017077:Culture Media, Conditioned; D016762:Genes, fos / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D007700:Kinetics; D008533:Megakaryocytes; D008623:Mercaptoethanol / Q000494:pharmacology; D051379:Mice; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D011759:Pyrrolidines; D017382:Reactive Oxygen Species / Q000737:chemistry*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019089:Stem Cell Factor / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D013926:Thrombopoietin / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D017077:Culture Media, Conditioned; D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; D016760:Proto-Oncogene Proteins c-fos; D011759:Pyrrolidines; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D008623:Mercaptoethanol; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013926:Thrombopoietin; D006861:Hydrogen Peroxide; D000111:Acetylcysteine