Abstract
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.
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Abbreviations
- HPCs:
-
hematopoietic progenitor cells
- NES:
-
nuclear export signal
- NLS:
-
nuclear localization signal
- CRM1/exportin1:
-
chromosome region maintenance1/exportin1
- FLC:
-
Friend erythroleukemia cells
- GFP:
-
green fluorescent protein
- RT-PCR:
-
reverse transcriptase polymerase chain reaction
- E:
-
erythroid
- MK:
-
megakaryocytic
- EBS:
-
ets binding site
- LMB:
-
leptomycin B
- IRES:
-
internal ribosome entry site
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Acknowledgements
This work was supported by institute fund from the Istituto Superiore di Sanità and Grant from the Italy-USA program on ‘Therapy of Tumors’. The authors gratefully acknowledge Stuart Orkin (Children’ Hospital, Boston, MA) and Vincenzo Zappavigna (University of Modena and Reggio Emilia, Modena, Italy) for providing reagents, Ruggero De Maria for critically reading the manuscript, Mariangela Fontana and Monica Blasi for editorial assistance and Alfonso Zito and Giuseppe Loreto for graphics.
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Lulli, V., Romania, P., Morsilli, O. et al. Overexpression of Ets-1 in human hematopoietic progenitor cells blocks erythroid and promotes megakaryocytic differentiation. Cell Death Differ 13, 1064–1074 (2006). https://doi.org/10.1038/sj.cdd.4401811
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DOI: https://doi.org/10.1038/sj.cdd.4401811
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