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Phosphatidylinositol 3-kinase/Akt induced by erythropoietin renders the erythroid differentiation factor GATA-1 competent for TIMP-1 gene transactivation.

The contribution of erythropoietin to the differentiation of the red blood cell lineage remains elusive, and the demonstration of a molecular link between erythropoietin and the transcription of genes associated with erythroid differentiation is lacking. In erythroid cells, expression of the tissue inhibitor of matrix metalloproteinase (TIMP-1) is strictly dependent on erythropoietin. We report here that erythropoietin regulates the transcription of the TIMP-1 gene upon binding to its receptor in erythroid cells by triggering the activation of phosphatidylinositol 3-kinase (PI3K)/Akt. We found that Akt directly phosphorylates the transcription factor GATA-1 at serine 310 and that this site-specific phosphorylation is required for the transcriptional activation of the TIMP-1 promoter. This chain of events can be recapitulated in nonerythroid cells by transfection of the implicated molecular partners, resulting in the expression of the normally silent endogenous TIMP-1 gene. Conversely, TIMP-1 secretion is profoundly decreased in erythroid cells from fetal livers of transgenic knock-in mice homozygous for a GATA(S310A) gene, which encodes a GATA-1 mutant that cannot be phosphorylated at Ser(310). Furthermore, retrovirus-mediated expression of GATA(S310A) into GATA-1(null)-derived embryonic stem cells decreases the rate of hemoglobinization by more than 50% compared to expressed wild-type GATA-1. These findings provide the first example of a chain of coupling mechanisms between the binding of erythropoietin to its receptor and GATA-1-dependent gene expression.

Pubmed ID: 16107690

Authors

  • Kadri Z
  • Maouche-Chretien L
  • Rooke HM
  • Orkin SH
  • Romeo PH
  • Mayeux P
  • Leboulch P
  • Chretien S

Journal

Molecular and cellular biology

Publication Data

September 18, 2005

Associated Grants

None

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Binding Sites
  • Cell Differentiation
  • Cells, Cultured
  • Cercopithecus aethiops
  • DNA-Binding Proteins
  • Erythroid Cells
  • Erythroid-Specific DNA-Binding Factors
  • Erythropoietin
  • GATA1 Transcription Factor
  • Humans
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Phosphatidylinositol 3-Kinases
  • Phosphoserine
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Receptors, Erythropoietin
  • Signal Transduction
  • Tissue Inhibitor of Metalloproteinase-1
  • Transcription Factors
  • Transcription, Genetic
  • Transcriptional Activation