The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1.
The transcription factor growth factor independence 1 (Gfi1) and the growth factor granulocyte colony-stimulating factor (G-CSF) are individually essential for neutrophil differentiation from myeloid progenitors. Here, we provide evidence that the functions of Gfi1 and G-CSF are linked in the regulation of granulopoiesis. We report that Gfi1 promotes the expression of Ras guanine nucleotide releasing protein 1 (RasGRP1), an exchange factor that activates Ras, and that RasGRP1 is required for G-CSF signaling through the Ras/mitogen-activated protein/extracellular signal-regulated kinase (MEK/Erk) pathway. Gfi1-null mice have reduced levels of RasGRP1 mRNA and protein in thymus, spleen, and bone marrow, and Gfi1 transduction in myeloid cells promotes RasGRP1 expression. When stimulated with G-CSF, Gfi1-null myeloid cells are selectively defective at activating Erk1/2, but not signal transducer and activator of transcription 1 (STAT1) or STAT3, and fail to differentiate into neutrophils. Expression of RasGRP1 in Gfi1-deficient cells rescues Erk1/2 activation by G-CSF and allows neutrophil maturation by G-CSF. These results uncover a previously unknown function of Gfi1 as a regulator of RasGRP1 and link Gfi1 transcriptional control to G-CSF signaling and regulation of granulopoiesis.
de la Luz Sierra
Maria
M
Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD, USA.
Sakakibara
Shuhei
S
Gasperini
Paola
P
Salvucci
Ombretta
O
Jiang
Kan
K
McCormick
Peter J
PJ
Segarra
Marta
M
Stone
Jim
J
Maric
Dragan
D
Zhu
Jinfang
J
Qian
Xiaolan
X
Lowy
Douglas R
DR
Tosato
Giovanna
G
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D007124:Immunoenzyme Techniques; D051379:Mice; D009504:Neutrophils / Q000166:cytology* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology*
D004268:DNA-Binding Proteins; C079873:Gfi1 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C112278:Rasgrp1 protein, mouse; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D050799:STAT5 Transcription Factor; D014157:Transcription Factors; D016179:Granulocyte Colony-Stimulating Factor; D048049:Extracellular Signal-Regulated MAP Kinases