Research Institute of Molecular Pathology (IMP), Dr. Bohr-Gasse 7, A-1030 Vienna, Austria.
Cell Res. 2012 Mar;22(3):539-50. doi: 10.1038/cr.2011.159. Epub 2011 Sep 27.
Enucleation of erythroblasts during terminal differentiation is unique to mammals. Although erythroid enucleation has been extensively studied, only a few genes, including retinoblastoma protein (Rb), have been identified to regulate nuclear extrusion. It remains largely undefined by which signaling molecules, the extrinsic stimuli, such as erythropoietin (Epo), are transduced to induce enucleation. Here, we show that p38α, a mitogen-activated protein kinase (MAPK), is required for erythroid enucleation. In an ex vivo differentiation system that contains high Epo levels and mimics stress erythropoiesis, p38α is activated during erythroid differentiation. Loss of p38α completely blocks enucleation of primary erythroblasts. Moreover, p38α regulates erythroblast enucleation in a cell-autonomous manner in vivo during fetal and anemic stress erythropoiesis. Markedly, loss of p38α leads to downregulation of p21, and decreased activation of the p21 target Rb, both of which are important regulators of erythroblast enucleation. This study demonstrates that p38α is a key signaling molecule for erythroblast enucleation during stress erythropoiesis.
红细胞在终末分化过程中的去核作用是哺乳动物所特有的。尽管已经广泛研究了红细胞去核作用，但只有少数基因（包括视网膜母细胞瘤蛋白（Rb））被鉴定为调节核外排。目前尚不清楚哪些信号分子（如促红细胞生成素（Epo）等外在刺激）被转导以诱导去核。在这里，我们表明，丝裂原活化蛋白激酶（MAPK）p38α是红细胞去核所必需的。在含有高 Epo 水平并模拟应激性红细胞生成的体外分化系统中，p38α在红细胞分化过程中被激活。p38α 的缺失完全阻止了原代红细胞的去核。此外，p38α 在体内胎儿和贫血应激性红细胞生成过程中以细胞自主的方式调节红细胞去核。值得注意的是，p38α 的缺失导致 p21 的下调和 p21 靶标 Rb 的活性降低，这两者都是红细胞去核的重要调节因子。这项研究表明，p38α 是应激性红细胞生成过程中红细胞去核的关键信号分子。
