Bakker Walbert J, Blázquez-Domingo Montserrat, Kolbus Andrea, Besooyen Janey, Steinlein Peter, Beug Hartmut, Coffer Paul J, Löwenberg Bob, von Lindern Marieke, van Dijk Thamar B
Dept. of Hematology, Erasmus MC, PO Box 1738, 3000 DR Rotterdam, Netherlands.
J Cell Biol. 2004 Jan 19;164(2):175-84. doi: 10.1083/jcb.200307056.
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.
红细胞生成需要对红系祖细胞的增殖、成熟和存活进行严格控制。由于磷脂酰肌醇-3-激酶（PI3K）的激活是促红细胞生成素/干细胞因子诱导红系祖细胞增殖所必需的，我们研究了PI3K控制的叉头转录因子O类（FoxO）亚家族的作用。在红系分化过程中，FoxO3a的表达和核内积累增加，而FoxO3a活性的过早诱导加速了红系祖细胞向红细胞的分化。我们确定B细胞易位基因1（BTG1）/抗增殖蛋白2为红系祖细胞中FoxO3a的靶基因。启动子研究表明BTG1是FoxO3a的直接靶标。BTG1在原代小鼠骨髓细胞中的表达阻断了红系集落的生长，这需要BTG1的一个与蛋白精氨酸甲基转移酶1结合的结构域。在红系分化过程中，精氨酸甲基化增加与BTG1的表达同时出现。一致地，甲基转移酶活性的抑制阻断了红系成熟，而不影响祖细胞的增殖。我们提出FoxO3a控制的BTG1表达以及随后对蛋白精氨酸甲基转移酶活性的调节是控制红系增殖和分化的一种新机制。
