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

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

doi:10.1182/blood-2009-10-246967

Cited by 42 publications

(25 citation statements)

References 42 publications

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“…Furthermore, Gfi‐1‐ knockout mice exhibit abnormal granulocytopoiesis with the absence of phenotypically mature neutrophils and loss of primary but not secondary granule expression in the neutrophilic lineages in the circulation . Gfi‐1 has also been shown to regulate the G‐CSF/GCSF‐R signaling by activating the Ras/MEK/Erk signaling pathway, ultimately contributing to the G‐CSF–induced neutrophil differentiation . Another important TF in neutrophil terminal differentiation is the lymphoid enhancer factor‐1 (Lef‐1), which is highly expressed in neutrophil progenitors.…”

Section: Granulocytopoiesismentioning

confidence: 99%

Transcriptional regulation of neutrophil differentiation and function during inflammation

Udalova

2020

Journal of Leukocyte Biology

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Neutrophils are the most abundant leukocytes in innate immunity where they elicit powerful effector functions to eliminate invading pathogens and modulate the adaptive as well as the innate immune response. Neutrophil function must be tightly regulated during inflammation and infection to avoid additional tissue damage. Increasing evidence suggests that transcription factors (TFs) function as key regulators to modulate transcriptional output, thereby controlling cell fate decision and the inflammatory responses. However, the molecular mechanisms underlying neutrophil differentiation and function during inflammation remain largely uncharacterized. Here, we provide a comprehensive overview of TFs known to be crucial for neutrophil maturation and in the signaling pathways that control neutrophil differentiation and activation. We also outline how emerging genomic and single‐cell technologies may facilitate further discovery of neutrophil transcriptional regulators.

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Section: Granulocytopoiesismentioning

confidence: 99%

Transcriptional regulation of neutrophil differentiation and function during inflammation

Udalova

2020

Journal of Leukocyte Biology

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“…5) (Diaz-Flores et al, 2013). A second report suggested that RasGRP1 couples to a related cytokine, G-CSF, to induce phospho-ERK that is important for neutrophil development (de la Luz Sierra et al, 2010). More recently, our group demonstrated that IL-7-induced RasGTP is RasGRP1-dependent in T cell leukemic cells (Hartzell et al, 2013).…”

Section: Multiple Receptor Systems Couple To Rasgrp Proteinsmentioning

confidence: 99%

“…A candidate regulator is a transcription factor Gfi1. It has been shown that Gfi1 knockout mice have deficiency in RasGRP1 mRNA and protein levels (de la Luz Sierra et al, 2010). Interestingly, a recent report by the Moroy group demonstrated that Gfi1 mRNA levels are increased in a subset of human T-ALL patients, which had a Notch1-like gene expression signature (Khandanpour et al, 2013).…”

Section: A Special Role For Rasgrp1; Expression or Biochemical Features?mentioning

confidence: 99%

RasGRP Ras guanine nucleotide exchange factors in cancer

2013

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Summary RasGRP proteins are activators of Ras and other related small GTPases by the virtue of functioning as guanine nucleotide exchange factors (GEFs). In vertebrates, four RasGRP family members have been described. RasGRP-1 through −4 share many structural domains but there are also subtle differences between each of the different family members. Whereas SOS RasGEFs are ubiquitously expressed, RasGRP proteins are expressed in distinct patterns, such as in different cells of the hematopoietic system and in the brain. Most studies have concentrated on the role of RasGRP proteins in the development and function of immune cell types because of the predominant RasGRP expression profiles in these cells and the immune phenotypes of mice deficient for Rasgrp genes. However, more recent studies demonstrate that RasGRPs also play an important role in tumorigenesis. Examples are skin- and hematological-cancers but also solid malignancies such as melanoma or prostate cancer. These novel studies bring up many new and unanswered questions related to the molecular mechanism of RasGRP-driven oncogenesis, such as new receptor systems that RasGRP appears to respond to as well as regulatory mechanism for RasGRP expression that appear to be perturbed in these cancers. Here we will review some of the known aspects of RasGRP biology in lymphocytes and will discuss the exciting new notion that RasGRP Ras exchange factors play a role in oncogenesis downstream of various growth factor receptors.

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“…Myeloid precursors from Gfi-1−/− mice are unable to differentiate into mature neutrophils in vitro , but instead give rise to atypical monocytes. In contrast, overexpression of Gfi-1 accelerates neutrophilic differentiation at the expense of monocytic differentiation (10, 11). These data reveal a critical role of Gfi-1 during early myeloid development i.e., promotion of neutrophilic differentiation in an instructive manner and suppression of the monocytic development.…”

Section: Introductionmentioning

confidence: 99%

Gfi-1 inhibits the expression of eosinophil major basic protein (MBP) during G-CSF-induced neutrophilic differentiation

Liu

Fan

2012

Int J Hematol

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The zinc finger transcriptional repressor Gfi-1 has been shown to play a critical role in early granulopoiesis; however, its role in late neutrophilic development is poorly understood. We report here that forced expression of a dominant negative Gfi-1 mutant, N382S, resulted in augmented mRNA levels of eosinophil major basic protein (MBP) in myeloid cells induced with G-CSF to undergo terminal neutrophilic differentiation. MBP is a cytotoxic protein that is abundantly expressed in eosinophils, but not in neutrophils. Ectopic expression of MBP inhibited the proliferation and survival of differentiating myeloid cells in response to G-CSF. Significantly, while GFI-1 is upregulated during neutrophilic differentiation, it is rapidly downregulated upon induction of eosinophilic differentiation, which was associated with increased MBP expression. Knockdown of GFI-1 in eosinophilic cells also led to increased level of MBP mRNA. These results indicate that Gfi-1 functions to inhibit the expression of MBP and aberrant expression of MBP as a result of loss of Gfi-1 function may cause premature apoptosis of differentiating neutrophils. In contrast, the rapid downregulation of Gfi-1 during eosinophilic development may allow for abundant expression of MBP, a hallmark of eosinophilic differentiation.

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

Cited by 42 publications

References 42 publications

Transcriptional regulation of neutrophil differentiation and function during inflammation

Transcriptional regulation of neutrophil differentiation and function during inflammation

RasGRP Ras guanine nucleotide exchange factors in cancer

Gfi-1 inhibits the expression of eosinophil major basic protein (MBP) during G-CSF-induced neutrophilic differentiation

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