FoxO3a regulates erythroid differentiation and induces BTG1, an activator of protein arginine methyl transferase 1

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.

FOXO3a Induces Differentiation of Bcr-Abl-transformed Cells through Transcriptional Down-regulation of Id1

“…Recently it has been shown that FOXO3a can play a role in erythroid differentiation through up-regulation of the B-cell translocation gene 1 protein (38). Bakker et al demonstrated that B-cell translocation gene 1 can modulate protein arginine methylation activity, which they propose is a novel mechanism regulating erythroid differentiation.…”

“…The Id transcriptional repressors have been suggested to act at the checkpoint at which undifferentiated progenitor cells make the commitment to terminal differentiation. Id1 expression is high in proliferating, undifferentiated cells, whereas its expression is down-regulated as cells differentiate (38,49,50). For example, ectopic expression of Id1 inhibits B-cell development and differentiation of muscle and mammary epithelial cells (42).…”

“…This regulation of p21 by E2A is antagonized by Id1, suggesting that Id1 may stimulate proliferation through antagonism of E2A-dependent p21 expression. The bHLH that is primarily expressed in hematopoietic cells is SCL/TAL1 (38). However, ectopic expression of SCL/TAL1 in the HL-60 granulocytic cell line resulted in enhanced proliferation, not differentiation (55).…”

“…sis, depending on the cell type (22,(35)(36)(37). However, recently a role for FOXOs in regulating differentiation of several cell types has been described (36,38). To identify novel transcriptional targets of FOXO3a that might be involved in hematopoiesis, we made use of a bone marrow-derived cell line (Ba/F3 cells) stably expressing an inducible form of active FOXO3a, in which all three PKB-phosphorylation sites were mutated to alanine, FOXO3a(A3):ER* (29).…”

Btg1 and Btg2 gene expression during early chick development

“…It is known that BTG2 is induced by NGF, FGF, IL-6, TPA, serum, EGF, and cAMP (Bradbury et al, 1991;Fletcher et al, 1991;Montagnoli et al, 1996) indicating that a number of stimuli triggering different transduction pathways can activate the transcription of this gene. Also Btg1 has been shown to be a direct target of different molecules, including T3 hormone (Rodier et al, 1999), Insuline-like Growth Factor 1 (IGF-1) (Vadgama et al, 2006), or FoxO3A (Bakker et al, 2004). These data, together with the wide distribution and cell types where these genes are expressed during development, suggest that their regulation is likely to be dependent on cell type and cellular context.…”