Department of Pediatrics, Institute of DNA Medicine, Jikei University School of Medicine, Tokyo, Japan.
Leuk Res. 2011 Mar;35(3):416-8. doi: 10.1016/j.leukres.2010.11.002. Epub 2010 Dec 15.
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 3-24h of culture with EPO and was associated with increases in c-myc mRNA after 1-3h, of c-Myc protein after 3-6h, and of human telomerase reverse transcriptase (hTERT) mRNA and hTERT protein after 6-24h. 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.
我们评估了促红细胞生成素（EPO）在人红白血病 JAS-REN-A 细胞中激活端粒酶的分子机制。EPO 培养 3-24 小时后，端粒酶活性增加 3-4 倍，与 1-3 小时后 c-myc mRNA 增加、3-6 小时后 c-Myc 蛋白增加、6-24 小时后人端粒酶逆转录酶（hTERT）mRNA 和 hTERT 蛋白增加相关。同时，EPO 诱导信号转导转录激活因子 5（STAT5）、AKT 和细胞外信号调节激酶（ERK）的磷酸化。EPO 诱导的端粒酶活性被 AG490、PD98059 和 LY294002 显著抑制。AG490 通过抑制 STAT5 和 AKT 磷酸化下调 c-myc 和 hTERT mRNA 表达。PD98059 也降低了 c-myc 和 hTERT 的表达并抑制了 ERK 磷酸化。然而，尽管抑制了 STAT5 和 AKT 磷酸化，LY294002 并没有抑制 c-myc 或 hTERT mRNA 的表达。这些结果表明，EPO 通过双调控激活 JAS-REN-A 细胞中的端粒酶：Janus 酪氨酸激酶 2/STAT5/c-Myc 促进 hTERT 基因转录，磷酸肌醇 3'-激酶/AKT 促进 hTERT 蛋白磷酸化。
