Fang Jing, Menon Madhu, Kapelle William, Bogacheva Olga, Bogachev Oleg, Houde Estelle, Browne Sarah, Sathyanarayana Pradeep, Wojchowski Don M
Program in Stem and Progenitor Cell Biology, Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
Blood. 2007 Oct 1;110(7):2361-70. doi: 10.1182/blood-2006-12-063503. Epub 2007 Jun 4.
Erythropoietin (EPO's) actions on erythroblasts are ascribed largely to survival effects. Certain studies, however, point to EPO-regulated proliferation. To investigate this problem in a primary system, Kit(pos)CD71(high) erythroblasts were prepared from murine bone marrow, and were first used in the array-based discovery of EPO-modulated cell-cycle regulators. Five cell-cycle progression factors were rapidly up-modulated: nuclear protein 1 (Nupr1), G1 to S phase transition 1 (Gspt1), early growth response 1 (Egr1), Ngfi-A binding protein 2 (Nab2), and cyclin D2. In contrast, inhibitory cyclin G2, p27/Cdkn1b, and B-cell leukemia/lymphoma 6 (Bcl6) were sharply down-modulated. For CYCLIN G2, ectopic expression also proved to selectively attenuate EPO-dependent UT7epo cell-cycle progression at S-phase. As analyzed in primary erythroblasts expressing minimal EPO receptor alleles, EPO repression of cyclin G2 and Bcl6, and induction of cyclin D2, were determined to depend on PY343 (and Stat5) signals. Furthermore, erythroblasts expressing a on PY-null EPOR-HM allele were abnormally distributed in G0/G1. During differentiation divisions, EPOR-HM Ter119(pos) erythroblasts conversely accumulated in S-phase and faltered in an apparent EPO-directed transition to G0/G1. EPO/EPOR signals therefore control the expression of select cell-cycle regulatory genes that are proposed to modulate stage-specific decisions for erythroblast cell-cycle progression.
促红细胞生成素（EPO）对成红细胞的作用主要归因于其存活效应。然而，某些研究指出EPO可调节细胞增殖。为了在原代系统中研究这个问题，从小鼠骨髓中制备了Kit阳性CD71高表达的成红细胞，并首次用于基于芯片的EPO调节的细胞周期调节因子的发现。五个细胞周期进展因子迅速上调：核蛋白1（Nupr1）、G1到S期转换1（Gspt1）、早期生长反应1（Egr1）、Ngfi-A结合蛋白2（Nab2）和细胞周期蛋白D2。相反，抑制性细胞周期蛋白G2、p27/Cdkn1b和B细胞淋巴瘤6（Bcl6）则急剧下调。对于细胞周期蛋白G2，异位表达也被证明可在S期选择性减弱EPO依赖的UT7epo细胞周期进展。在表达最小EPO受体等位基因的原代成红细胞中进行分析，确定EPO对细胞周期蛋白G2和Bcl6的抑制以及对细胞周期蛋白D2的诱导依赖于PY343（和Stat5）信号。此外，表达PY缺失的EPOR-HM等位基因的成红细胞在G0/G1期分布异常。在分化分裂过程中，EPOR-HM Ter119阳性的成红细胞反而在S期积累，并在明显由EPO引导的向G0/G1期的转变中停滞不前。因此，EPO/EPOR信号控制着特定细胞周期调节基因的表达，这些基因被认为可调节成红细胞细胞周期进展的阶段特异性决定。
