Maturation Stage-specific Regulation of Megakaryopoiesis by Pointed-domain Ets Proteins.
From: Children’s Hospital of Philadelphia, ARC 316H, 3165 Civic Center Blvd, Philadelphia, PA, USA.
Blood
- Publish Date: Oct 2006
- ISSN: 0006-4971
- Volume: 108
- Issue: 7
- Pages: 2198-206
- Medium: Print
- Language: English
- Citation (JAMA): Pang Liyan, Xue Hai-Hui, Szalai Gabor, et al. Maturation Stage-specific Regulation of Megakaryopoiesis by Pointed-domain Ets Proteins.. Blood Oct 2006;108:2198-206
Abstract
Numerous megakaryocyte-specific genes contain signature Ets-binding sites in their regulatory regions. Fli-1 (friend leukemia integration 1), an Ets transcription factor, is required for the normal maturation of megakaryocytes and controls the expression of multiple megakaryocyte-specific genes. However, in Fli-1-/- mice, early megakaryopoiesis persists, and the expression of the early megakaryocyte-specific genes, alphaIIb and cMpl, is maintained, consistent with functional compensation by a related Ets factor(s). Here we identify the Ets protein GABPalpha (GA-binding protein alpha) as a regulator of early megakaryocyte-specific genes. Notably, GABPalpha preferentially occupies Ets elements of early megakaryocyte-specific genes in vitro and in vivo, whereas Fli-1 binds both early and late megakaryocyte-specific genes. Moreover, the ratio of GABPalpha/Fli-1 expression declines throughout megakaryocyte maturation. Consistent with this expression pattern, primary fetal liver-derived megakaryocytes from Fli-1-deficient murine embryos exhibit reduced expression of genes associated with late stages of maturation (glycoprotein [GP] Ibalpha, GPIX, and platelet factor 4 [PF4]), whereas GABPalpha-deficient megakaryocytes were mostly impaired in the expression of early megakaryocyte-specific genes (alphaIIb and cMpl). Finally, mechanistic experiments revealed that GABPalpha, like Fli-1, can impart transcriptional synergy between the hematopoietic transcription factor GATA-1 and its cofactor FOG-1 (friend of GATA-1). In concert, these data reveal disparate, but overlapping, functions of Ets transcription factors at distinct stages of megakaryocyte maturation.
Mesh Headings (Keywords): Animals, Binding Sites, COS Cells, Cercopithecus aethiops, Liver, Megakaryocytes, Mice, Mice, Inbred C57BL, Mice, Transgenic, NIH 3T3 Cells, Proto-Oncogene Protein c-ets-1, Proto-Oncogene Protein c-fli-1, Transcription, Genetic
Check for Full Text / PubMed Unique Identifier (PMID): 16757682
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