The Transcriptional Repressor GFI-1 Antagonizes PU.1 Activity through Protein-Protein Interaction

Abstract

Mice lacking the zinc finger transcriptional repressor protein GFI-1 are neutropenic. These mice generate abnormal immature myeloid cells exhibiting characteristics of both macrophages and granulocytes. Furthermore, Gfi-1 ؊/؊ mice are highly susceptible to bacterial infection. Interestingly, Gfi-1 ؊/؊ myeloid cells overexpress target genes of the PU.1 transcription factor such as the macrophage colony-stimulating factor receptor and PU.1 itself. We therefore determined whether GFI-1 modulates the transcriptional activity of PU.1. Our data demonstrate that GFI-1 physically interacts with PU

Transcriptional control of granulocyte and monocyte development

“…The same study found that Gfi-1 represses the Egr-2 promoter, providing cross-inhibition that stabilizes the neutrophil fate. Gfi-1 also directly interacts with and represses trans-activation by PU.1, providing an additional mechanism favoring granulopoiesis (Dahl et al, 2007).…”

Gfi1 and Gfi1b: key regulators of hematopoiesis

“…15,18,29,32 Gfi1 and Gfi1b also interact physically with other transcription factors through their zinc fingers to co-regulate gene expression (Figures 1 and 2). 17,29,[33][34][35][36] For example, Gfi1 interacts directly with ETS1 to repress the Bax gene through adjacent DNA binding sites. 33 Gfi1 may also mediate repression independently of DNA binding through interactions with the transcription factors Miz-1 and Pu.1.…”

“…33 Gfi1 may also mediate repression independently of DNA binding through interactions with the transcription factors Miz-1 and Pu.1. 34,35 Similarly, Gfi1b controls the activity of the transcription factor GATA1 through direct protein-protein interactions on the DNA. 17,37 Apart from transcription regulation, Gfi1 also regulates protein expression at another level.…”

“…20,50 However, Gfi1 also inhibits Pu.1 by direct repression of the Pu.1 gene 20 and by counteracting Pu.1 function through a protein-protein interaction. 35 In contrast, Pu.1 enhances the expression of transcription factors that inhibit Gfi1 gene expression. 50 Thus, loss of Gfi1 Abbreviations: CSF, colony-stimulating factor; EGR, early growth response gene; GATA, globin transcription factor; GM-CSF, granulocytemacrophage colony-stimulating factor; Gfi1, growth factor independence 1; HMGB2, high-mobility group-at-hook 2; HOXA-10, homeobox 10; iD1, inhibitor of DNA-binding 1; IL, interleukin; LPS, lipopolysaccharide; PLZF, promyeleocytic leukemia zinc finger; T-cell, thymus cells; TGF-b, transforming growth factor-b.…”

Ski can negatively regulates macrophage differentiation through its interaction with PU.1

“…Luciferase reporter assays QT6 or HEK293 cells on 24-well plates were transfected with PUx3-TK81-Luc (Ano et al, 2004), pFR-Luc (Stratagene, La Jolla, CA, USA) or pGL3-M-CSFR-Luc (Dahl et al, 2007) luciferase reporter construct (50 ng/well), together with effector plasmids (DEB-PU.1 (Ano et al, 2004), pCMV-T7-wtcSki, pCMV-T7-mt-cSki, pM or pM-PU.1) as indicated in the figure legend. The total amount of transfected DNA was equalized with pEGFP-C1 (vector, Clontech).…”