Terme J-M, Mocquet V, Kuhlmann A-S, Zane L, Mortreux F, Wattel E, Duc Dodon M, Jalinot P
Laboratoire de Biologie Moléculaire de la Cellule, Unité Mixte de Recherche 5239, Centre National de la Recherche Scientifique, Ecole Normale Supérieure de Lyon, Institut Fédératif de Recherche, Lyon cedex 07, France.
Leukemia. 2009 Nov;23(11):2081-9. doi: 10.1038/leu.2009.131. Epub 2009 Jul 9.
Telomerase activity, which has fundamental roles in development and carcinogenesis, strongly depends on the expression of human telomerase reverse transcriptase (hTERT), its catalytic subunit. In this report, we show that the basic helix-loop-helix factor, TAL1 (T-cell acute lymphoblastic leukemia 1), is a negative regulator of the hTERT promoter. Indeed, TAL1 overexpression leads to a decrease in hTERT mRNA abundance and hence to reduced telomerase activity. Conversely, suppression of TAL1 by RNA interference in Jurkat cells increases hTERT expression. Analysis by chromatin immunoprecipitation assays showed that TAL1 binds to the hTERT proximal promoter and recruits HDAC1. Considering the relationship recently established between TAL1 and the human T-cell leukemia virus type 1 (HTLV-1) Tax protein, which was confirmed in T lymphocyte clones derived from adult T-cell leukemia patients, we analyzed the effect of TAL1 with respect to the earlier characterized effects of Tax and HBZ (HTLV-1 basic leucine zipper) on hTERT expression. TAL1 was observed to reinforce the negative effect of Tax, whereas hTERT transactivation by the HBZ-JunD complex was repressed by TAL1 overexpression. Moreover, HBZ was found to induce proteasome-mediated degradation of TAL1. These observations support a model in which Tax and TAL1 by repressing hTERT would initially favor genomic instability, whereas expression of factors such as HBZ allows at a later stage an increase in hTERT production and consequently in telomerase activity.
端粒酶活性在发育和致癌过程中发挥着重要作用，它强烈依赖于其催化亚基人端粒酶逆转录酶（hTERT）的表达。在本报告中，我们表明碱性螺旋-环-螺旋因子TAL1（T细胞急性淋巴细胞白血病1）是hTERT启动子的负调控因子。事实上，TAL1的过表达导致hTERT mRNA丰度降低，从而导致端粒酶活性降低。相反，在Jurkat细胞中通过RNA干扰抑制TAL1可增加hTERT表达。染色质免疫沉淀分析表明，TAL1与hTERT近端启动子结合并募集HDAC1。考虑到最近在源自成人T细胞白血病患者的T淋巴细胞克隆中证实的TAL1与1型人类T细胞白血病病毒（HTLV-1）Tax蛋白之间的关系，我们分析了TAL1对Tax和HBZ（HTLV-1碱性亮氨酸拉链）早期表征的对hTERT表达影响的作用。观察到TAL1增强了Tax的负面影响，而TAL1过表达抑制了HBZ-JunD复合物对hTERT的反式激活。此外，发现HBZ可诱导蛋白酶体介导的TAL1降解。这些观察结果支持了一个模型，其中Tax和TAL1通过抑制hTERT最初会促进基因组不稳定，而HBZ等因子的表达在后期会导致hTERT产生增加，从而导致端粒酶活性增加。
