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Molecular and Cellular Biology, September 2005, p. 7412-7422, Vol. 25, No. 17
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.17.7412-7422.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Zahra Kadri,1 Leila Maouche-Chretien,1,2 Heather M. Rooke,3 Stuart H. Orkin,3 Paul-Henri Romeo,1 Patrick Mayeux,1 Philippe Leboulch,2 and Stany Chretien1,2*

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 GATAS310A gene, which encodes a GATA-1 mutant that cannot be phosphorylated at Ser310. Furthermore, retrovirus-mediated expression of GATAS310A into GATA-1null-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.

* Corresponding author. Mailing address: Division of Genetics, Brigham & Women's Hospital, Harvard Medical School New Research Building, Rm. 455, 77 Avenue Louis Pasteur, Boston, MA 02115. Phone: (617) 525-4762. Fax: (617) 525-4705. E-mail: schretien{at}rics.bwh.harvard.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, September 2005, p. 7412-7422, Vol. 25, No. 17
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.17.7412-7422.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Rimmele, P., Kosmider, O., Mayeux, P., Moreau-Gachelin, F., Guillouf, C. (2007). Spi-1/PU.1 participates in erythroleukemogenesis by inhibiting apoptosis in cooperation with Epo signaling and by blocking erythroid differentiation. Blood 109: 3007-3014 [Abstract] [Full Text]  
  • Rooke, H. M., Orkin, S. H. (2006). Phosphorylation of Gata1 at serine residues 72, 142, and 310 is not essential for hematopoiesis in vivo. Blood 107: 3527-3530 [Abstract] [Full Text]  
  • Blobel, G. A. (2006). GATA-1 caught in the AKT. Blood 107: 851a-852 [Full Text]  


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