Erythropoietin activates telomerase through transcriptional and posttranscriptional regulation in human erythroleukemic JAS-REN-A cells
Erythropoietin activates telomerase through transcriptional and posttranscriptional regulation in human erythroleukemic JAS-REN-A cells
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DOI：
10.1016/j.leukres.2010.11.002
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发表时间：
2011-03-01
影响因子：
2.7
通讯作者：
Yamada, Hisashi
中科院分区：
文献类型：
--
作者：
Akiyama, Masaharu;Kawano, Takeshi;Yamada, Hisashi
本研究探讨了促红细胞生成素（EPO）激活人红白血病JAS-REN-A细胞端粒酶活性的分子机制。EPO培养3-24 h后端粒酶活性增加3-4倍，并与1-3 h后c-myc mRNA、3-6 h后c-Myc蛋白以及6-24 h后人端粒酶逆转录酶（hTERT）mRNA和hTERT蛋白的增加相关。同时，EPO诱导信号转导转录激活因子5（STAT 5）、AKT和细胞外信号调节激酶（ERK）的磷酸化。AG 490、PD 98059和LY 294002可显著抑制EPO诱导的端粒酶活性。AG 490下调c-myc和hTERT mRNA表达，抑制STAT 5和AKT磷酸化。PD 98059还降低c-myc和hTERT表达并抑制ERK磷酸化。然而，LY 294002不抑制c-myc或hTERT mRNA的表达，尽管抑制STAT 5和AKT磷酸化。这些结果表明，EPO通过双重调节激活JAS-REN-A细胞中的端粒酶：通过Janus酪氨酸激酶2/STAT 5/c-Myc的hTERT基因转录和通过磷脂酰肌醇3 '-激酶/AKT的hTERT蛋白磷酸化。(C)2010爱思唯尔有限公司版权所有。
We evaluated the molecular mechanism of telomerase activation by erythropoietin (EPO) in human erythroleukemic JAS-REN-A cells. Telomerase activity increased 3-4 fold after 3-24 h of culture with EPO and was associated with increases in c-myc mRNA after 1-3 h, of c-Myc protein after 3-6 h, and of human telomerase reverse transcriptase (hTERT) mRNA and hTERT protein after 6-24 h. Simultaneously EPO induced phosphorylation of signal transducer activator of transcription 5 (STAT5), AKT, and extracellular signal-regulated kinase (ERK). Telomerase activity induced by EPO was significantly inhibited by AG490, PD98059, and LY294002. AG490 downregulated c-myc and hTERT mRNA expression with inhibited STAT5 and AKT phosphorylation. PD98059 also reduced c-myc and hTERT expression and inhibited ERK phosphorylation. However, LY294002 did not inhibit c-myc or hTERT mRNA expression despite inhibiting STAT5 and AKT phosphorylation. These results suggest that EPO activates telomerase in JAS-REN-A cells through dual regulation: hTERT gene transcription by Janus tyrosine kinase 2/STAT5/c-Myc and hTERT protein phosphorylation by phosphatidylinositol 3'-kinase/AKT. (C) 2010 Elsevier Ltd. All rights reserved.