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

Maria de la Luz Sierra, Shuhei Sakakibara, Paola Gasperini, Ombretta Salvucci, Kan Jiang, Peter J. McCormick, Marta Segarra, Jim Stone, Dragan Maric, Jinfang Zhu, Xiaolan Qian, Douglas R. Lowy, Giovanna Tosato

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)3970-3979
Number of pages10
JournalBlood
Volume115
Issue number19
DOIs
Publication statusPublished - 13 May 2010

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