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.
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
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
Mol. Cell. Biol.
Date: Sep. 01, 2005
PubMed ID: 16107690
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