The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1

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de la Luz Sierra, Maria, Sakakibara, Shuhei, Gasperini, Paola, Salvucci, Ombretta, Jiang, Kan, McCormick, Peter J., Segarra, Marta, Stone, Jim, Maric, Dragan, Zhu, Jinfang, Qian, Xiaolan, Lowy, Douglas R. and Tosato, Giovanna (2010) The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1. Blood, 115 (19). pp. 3970-3979. ISSN 0006-4971

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Abstract

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.

Item Type:	Article
Faculty \ School:	Faculty of Science > School of Pharmacy Faculty of Science > School of Environmental Sciences
Related URLs:	http://www.scopus.com/inward/record.url?...
Depositing User:	Pure Connector
Date Deposited:	13 Jan 2014 13:32
Last Modified:	24 Oct 2022 05:57
URI:	https://ueaeprints.uea.ac.uk/id/eprint/47158
DOI:	10.1182/blood-2009-10-246967

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