Yamada Osamu, Ozaki Kohji, Nakatake Mayuka, Akiyama Masaharu, Kawauchi Kiyotaka, Matsuoka Rumiko
Department of Hematology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan.
J Leukoc Biol. 2008 May;83(5):1240-8. doi: 10.1189/jlb.1207848. Epub 2008 Feb 14.
Using three different differentiation agents (1alpha, 25 dihydroxyvitamin D3, all-trans-retinoic acid, and Am80), down-regulation of telomerase activity was found to be a common response during the monocytic or granulocytic differentiation of human acute myeloblastic leukemia cell line 60 (HL60) cells. Rapid down-regulation of telomerase transcription occurred during early differentiation of HL60 cells prior to G(1) arrest. Akt kinase activity was suppressed after 6 h of differentiation along with inhibition of telomerase activity, and the extent of the suppression that occurred while maintaining telomerase protein expression suggested the post-translational regulation of telomerase activity. Recombinant Akt dose-dependently increased telomerase activity, and telomerase was inhibited at the transcriptional and post-translational levels by LY294002, suggesting that PI-3K/Akt is one of the key signaling proteins involved in telomerase regulation. Each of the three differentiation agents caused a significant increase of signaling proteins (including Akt) at 3 days after the initiation of differentiation. Changes of acetyl-histone H4, which regulates transcription of the telomerase gene, were observed before the activation of Akt. This finding suggests that epigenetic control of telomerase transcription occurs before activation of Akt during the late stage of differentiation. These results indicate that telomerase activity is regulated by at least two mechanisms during granulocytic and monocytic differentiation, with one mechanism being transcriptional and the other being post-translational.
使用三种不同的分化剂（1α,25-二羟基维生素D3、全反式维甲酸和Am80），发现端粒酶活性的下调是人类急性髓性白血病细胞系60（HL60）细胞单核细胞或粒细胞分化过程中的常见反应。在HL60细胞早期分化至G(1)期停滞之前，端粒酶转录迅速下调。分化6小时后端粒酶活性受到抑制，同时Akt激酶活性也被抑制，在维持端粒酶蛋白表达的情况下所发生的抑制程度表明端粒酶活性存在翻译后调控。重组Akt剂量依赖性地增加端粒酶活性，LY294002在转录和翻译后水平抑制端粒酶，这表明PI-3K/Akt是参与端粒酶调控的关键信号蛋白之一。三种分化剂中的每一种在分化开始3天后都会导致信号蛋白（包括Akt）显著增加。在Akt激活之前观察到了调节端粒酶基因转录的乙酰化组蛋白H4的变化。这一发现表明，在分化后期，端粒酶转录的表观遗传控制发生在Akt激活之前。这些结果表明，在粒细胞和单核细胞分化过程中端粒酶活性至少受两种机制调控，一种机制是转录调控，另一种是翻译后调控。
