PMID:14734530

Citation	Bakker, WJ, Blázquez-Domingo, M, Kolbus, A, Besooyen, J, Steinlein, P, Beug, H, Coffer, PJ, Löwenberg, B, von Lindern, M and van Dijk, TB (2004) FoxO3a regulates erythroid differentiation and induces BTG1, an activator of protein arginine methyl transferase 1. J. Cell Biol. 164:175-84
Abstract	Erythropoiesis requires tight control of expansion, maturation, and survival of erythroid progenitors. Because activation of phosphatidylinositol-3-kinase (PI3K) is required for erythropoietin/stem cell factor-induced expansion of erythroid progenitors, we examined the role of the PI3K-controlled Forkhead box, class O (FoxO) subfamily of Forkhead transcription factors. FoxO3a expression and nuclear accumulation increased during erythroid differentiation, whereas untimely induction of FoxO3a activity accelerated differentiation of erythroid progenitors to erythrocytes. We identified B cell translocation gene 1 (BTG1)/antiproliferative protein 2 as a FoxO3a target gene in erythroid progenitors. Promoter studies indicated BTG1 as a direct target of FoxO3a. Expression of BTG1 in primary mouse bone marrow cells blocked the outgrowth of erythroid colonies, which required a domain of BTG1 that binds protein arginine methyl transferase 1. During erythroid differentiation, increased arginine methylation coincided with BTG1 expression. Concordantly, inhibition of methyl transferase activity blocked erythroid maturation without affecting expansion of progenitor cells. We propose FoxO3a-controlled expression of BTG1 and subsequent regulation of protein arginine methyl transferase activity as a novel mechanism controlling erythroid expansion and differentiation.
Links	PubMed PMC2172323 Online version:10.1083/jcb.200307056
Keywords	3T3 Cells; Animals; Base Sequence; COS Cells; Cell Differentiation/physiology; Cell Line; Cells, Cultured; Cercopithecus aethiops; Cloning, Molecular; DNA Primers; Enzyme Activation; Forkhead Transcription Factors; Genes, Reporter; Hematopoietic Stem Cells/cytology; Hematopoietic Stem Cells/physiology; Humans; Luciferases/genetics; Mice; Molecular Sequence Data; Neoplasm Proteins/genetics; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Promoter Regions, Genetic; Protein-Arginine N-Methyltransferases/metabolism; Transcription Factors/genetics; Transcription Factors/physiology
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