Loss of interleukin-2-dependency in HTLV-I-infected T cells on gene silencing of thioredoxin-binding protein-2
Loss of interleukin-2-dependency in HTLV-I-infected T cells on gene silencing of thioredoxin-binding protein-2
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DOI：
10.1038/sj.onc.1209256
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发表时间：
2006-04-01
期刊：
影响因子：
8
通讯作者：
Yodoi, J
中科院分区：
文献类型：
--
作者：
Ahsan, MK;Masutani, H;Yodoi, J
从依赖白细胞介素-2 （IL-2）到不依赖IL-2生长的转变被认为是人类T细胞白血病病毒i型（HTLV-I）感染T细胞转化的关键步骤之一。在htlv -i感染的t细胞系转化过程中，硫氧还蛋白结合蛋白-2 （TBP-2）的表达缺失。在体外模型中，我们分析了TBP-2表达缺失的机制以及TBP-2在il -2依赖性生长中的作用，以研究HTLV-I的多步骤转化。TBP-2基因中的CpGs在il -2非依赖性细胞中甲基化，而在il -2依赖性细胞中不甲基化。5-aza-2'-脱氧胞苷和组蛋白去乙酰化酶抑制剂的连续治疗增加了组蛋白乙酰化和TBP-2的表达，表明TBP-2表达的丧失是由于DNA甲基化和组蛋白去乙酰化。在依赖IL-2的细胞中，与细胞生长相关的IL-2维持了TBP-2的基础表达水平，而与生长抑制相关的IL-2剥夺则上调了TBP-2的表达。在IL-2非依赖性细胞中过表达TBP-2可抑制细胞生长并部分恢复对IL-2的反应性。TBP-2的敲低导致IL-2依赖性细胞在没有IL-2的情况下部分生长。这些结果表明，表观遗传沉默TBP-2基因导致对IL- 2的反应性丧失，导致htlv -i感染的t细胞系中不受控制的IL- 2非依赖性生长。
The transition from interleukin-2 (IL-2)-dependent to IL-2-independent growth is considered one of the key steps in the transformation of human T-cell leukemia virus type-I (HTLV-I)-infected T cells. The expression of thioredoxin-binding protein-2 (TBP-2) is lost during the transition of HTLV-I-infected T-cell lines. Here, we analysed the mechanism of loss of TBP-2 expression and the role of TBP-2 in IL-2-dependent growth in the in vitro model to investigate multistep transformation of HTLV-I. CpGs in the TBP-2 gene are methylated in IL-2-independent but not in IL-2-dependent cells. Sequential treatment with 5-aza-2'-deoxycytidine and a histone deacetylase inhibitor augmented histone acetylation and TBP-2 expression, suggesting that loss of TBP-2 expression is due to DNA methylation and histone deacetylation. In IL-2-dependent cells, a basal level of TBP-2 expression was maintained by IL-2 associated with cellular growth, whereas TBP-2 expression was upregulated on deprivation of IL-2 associated with growth suppression. Overexpression of TBP-2 in IL-2-independent cells suppressed the growth and partially restored responsiveness to IL-2. Knockdown of TBP-2 caused the IL-2-dependent cells to show partial growth without IL- 2. These results suggested that epigenetic silencing of the TBP-2 gene results in a loss of responsiveness to IL- 2, contributing to uncontrolled IL- 2- independent growth in HTLV-I-infected T-cell lines.