Gfi-1B controls human erythroid and megakaryocytic differentiation by regulating TGF-beta signaling at the bipotent erythro-megakaryocytic progenitor stage

Blood. 2010 Apr 8;115(14):2784-95. doi: 10.1182/blood-2009-09-241752. Epub 2010 Feb 2.

Abstract

Growth factor independence-1B (Gfi-1B) is a transcriptional repressor essential for erythropoiesis and megakaryopoiesis. Targeted gene disruption of GFI1B in mice leads to embryonic lethality resulting from failure to produce definitive erythrocytes, hindering the study of Gfi-1B function in adult hematopoiesis. We here show that, in humans, Gfi-1B controls the development of erythrocytes and megakaryocytes by regulating the proliferation and differentiation of bipotent erythro-megakaryocytic progenitors. We further identify in this cell population the type III transforming growth factor-beta receptor gene, TGFBR3, as a direct target of Gfi-1B. Knockdown of Gfi-1B results in altered transforming growth factor-beta (TGF-beta) signaling as shown by the increase in Smad2 phosphorylation and its inability to associate to the transcription intermediary factor 1-gamma (TIF1-gamma). Because the Smad2/TIF1-gamma complex is known to specifically regulate erythroid differentiation, we propose that, by repressing TGF-beta type III receptor (TbetaRIotaII) expression, Gfi-1B favors the Smad2/TIF1-gamma interaction downstream of TGF-beta signaling, allowing immature progenitors to differentiate toward the erythroid lineage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Apoptosis Regulatory Proteins / metabolism
  • Cell Differentiation / physiology*
  • Cell Proliferation
  • Erythrocytes / cytology
  • Erythrocytes / metabolism*
  • Erythropoiesis / physiology
  • Gene Expression Regulation / physiology
  • Humans
  • K562 Cells
  • Megakaryocyte-Erythroid Progenitor Cells / cytology
  • Megakaryocyte-Erythroid Progenitor Cells / metabolism
  • Megakaryocytes / cytology
  • Megakaryocytes / metabolism*
  • Multiprotein Complexes / metabolism
  • Nuclear Proteins / metabolism
  • Phosphorylation / physiology
  • Proteoglycans / metabolism
  • Proto-Oncogene Proteins / metabolism*
  • Receptors, Transforming Growth Factor beta / metabolism
  • Repressor Proteins / metabolism*
  • Signal Transduction / physiology*
  • Smad2 Protein / metabolism
  • Thrombopoiesis / physiology
  • Transforming Growth Factor beta / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • GFI1B protein, human
  • Multiprotein Complexes
  • Nuclear Proteins
  • Proteoglycans
  • Proto-Oncogene Proteins
  • Receptors, Transforming Growth Factor beta
  • Repressor Proteins
  • SMAD2 protein, human
  • Smad2 Protein
  • TIAF1 protein, human
  • Transforming Growth Factor beta
  • betaglycan