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

Content Provider	PubMed Central
Author	Kadri, Zahra Maouche-chretien, Leila Rooke, Heather M. Orkin, Stuart H. Romeo, Paul-henri Mayeux, Patrick Philippe, Leboulch Chretien, Stany
Copyright Year	2005
Abstract	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.
Related Links	http://dx.doi.org/10.1128/mcb.25.17.7412-7422.2005
Ending Page	7422
Page Count	11
Starting Page	7412
File Format	PDF
ISSN	02707306
e-ISSN	10985549
Journal	Molecular and Cellular Biology
Issue Number	17
Volume Number	25
Language	English
Publisher	American Society for Microbiology
Publisher Date	2005-09-01
Access Restriction	Open
Rights Holder	American Society for Microbiology
Subject Keyword	Cell Biology Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Biology

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