title: Roles of Stat3 and ERK in G-CSF signaling.
abstract: G-CSF specifically stimulates the proliferation and differentiation of cells that are committed to the neutrophil-granulocyte lineage. Although Stat3 was thought to be essential for the transduction of G-CSF-induced cell proliferation and differentiation signals, mice deficient for Stat3 in hematopoietic cells show neutrocytosis and infiltration of cells into the digestive tract. The number of progenitor cells in the neutrophil lineage is not changed, and G-CSF-induced proliferation of progenitor cells and prolonged neutrophil survival were observed in Stat3-deficient mice. In hematopoietic cells from Stat3-deficient mice, trace levels of SOCS3, a negative regulator of granulopoiesis, were observed, and SOCS3 expression was not induced by G-CSF stimulation. Stat3-null bone marrow cells displayed a significant activation of extra-cellular regulated kinase 1 (ERK1)/ERK2 under basal conditions, and the activation of ERK was enhanced and sustained by G-CSF stimulation. Furthermore, the augmented proliferation of Stat3-deficient bone marrow cells in response to G-CSF was dramatically decreased by addition of a MEK1 inhibitor. These results indicate that Stat3 functions as a negative regulator of G-CSF signaling by inducing SOCS3 expression and that ERK activation is the major factor responsible for inducing the proliferation of hematopoietic cells in response to G-CSF.
authors.affiliation: The First Department of Internal Medicine, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
authors.forename: Kenjirou
authors.initials: K
authors.lastname: Kamezaki
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shimoda
authors.forename: Akihiko
authors.initials: A
authors.lastname: Numata
authors.forename: Takashi
authors.initials: T
authors.lastname: Haro
authors.forename: Haruko
authors.initials: H
authors.lastname: Kakumitsu
authors.forename: Masumi
authors.initials: M
authors.lastname: Yoshie
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsuda
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Ogawa
authors.forename: Mine
authors.initials: M
authors.lastname: Harada
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000502:physiology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D015534:Trans-Activators / Q000172:deficiency / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016179:Granulocyte Colony-Stimulating Factor; D048049:Extracellular Signal-Regulated MAP Kinases