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Phosphatidylinositol 3-Kinase/Akt Induced by Erythropoietin Renders the Erythroid Differentiation Factor GATA-1 Competent for TIMP-1 Gene Transactivation

Département d'Hématologie, Institut Cochin, INSERM U567, CNRS UMR 8104, Université René Descartes Hopital Cochin, 75014 Paris, France,¹ Genetics Division, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115,² Division of Hematology/Oncology, Children's Hospital, and Dana Farber Cancer Institute, Harvard Medical School, and Howard Hughes Medical Institute, Boston, Massachusetts 02115³

Received 16 May 2005/ Accepted 8 June 2005

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 Ser³¹⁰. 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.

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