Overexpression of Ets-1 in human hematopoietic progenitor cells blocks erythroid and promotes megakaryocytic differentiation.
Ets-1 is a widely expressed transcription factor implicated in development, tumorigenesis and hematopoiesis. We analyzed Ets-1 gene expression during human erythroid and megakaryocytic (MK) differentiation in unilineage cultures of CD34+ progenitor cells. During erythroid maturation, Ets-1 is downmodulated and exported from the nucleus into the cytoplasm through an active mechanism mediated by a leucine-rich nuclear export signal. In contrast, during megakaryocytopoiesis Ets-1 increases and remains localized in the nucleus up to terminal maturation. Overexpression of Ets-1 in erythroid cells blocks maturation at the polychromatophilic stage, increases GATA-2 and decreases both GATA-1 and erythropoietin receptor expression. Conversely, Ets-1 overexpressing megakaryocytes are characterized by enhanced differentiation and maturation, coupled with upmodulation of GATA-2 and megakaryocyte-specific genes. We show that Ets-1 binds to and activates the GATA-2 promoter, in vitro and in vivo, indicating that one of the pathways through which Ets-1 blocks erythroid and promotes MK differentiation is via upmodulation of GATA-2 expression.
Lulli
V
V
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
Romania
P
P
Morsilli
O
O
Gabbianelli
M
M
Pagliuca
A
A
Mazzeo
S
S
Testa
U
U
Peschle
C
C
Marziali
G
G
D021581:Active Transport, Cell Nucleus; D000328:Adult; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D041905:Erythroid Cells / Q000166:cytology* / Q000378:metabolism; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D049790:Nuclear Export Signals / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018952:Antigens, CD34; C494041:ETS1 protein, human; D050982:GATA1 Transcription Factor; D050989:GATA2 Transcription Factor; D049790:Nuclear Export Signals; D050784:Proto-Oncogene Protein c-ets-1