The transcriptional repressor GFI-1 antagonizes PU.1 activity through protein-protein interaction

Richard Dahl, Sangeeta R. Iyer, Kristin S. Owens, Dorothy D. Cuylear, M. Celeste Simon

Research output: Contribution to journalArticle

57 Scopus citations

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.1, repressing PU.1-dependent transcription. This repression is functionally significant, as GFI-1 blocked PU.1-induced macrophage differentiation of a multipotential hematopoietic progenitor cell line. Retroviral expression of GFI-1 in primary murine hematopoietic progenitors increased granulocyte differentiation at the expense of macrophage differentiation. We interbred Gfi-1-/- and PU.1-/- mice and observed that heterozygosity at the PU.1 locus partially rescued the Gfi-1-/- mixed myeloid lineage phenotype, but failed to restore granulocyte differentiation. Our data demonstrate that GFI-1 represses PU.1 activity and that lack of this repression in Gfi-1-/- myeloid cells contributes to the observed mixed lineage phenotype.

Original languageEnglish (US)
Pages (from-to)6473-6483
Number of pages11
JournalJournal of Biological Chemistry
Volume282
Issue number9
DOIs
StatePublished - Mar 2 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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