Complex cell cycle abnormalities caused by human T-lymphotropic virus type 1 Tax.
Complex cell cycle abnormalities caused by human T-lymphotropic virus type 1 Tax.
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由人类 T 淋巴细胞病毒 1 型 Tax 引起的复杂细胞周期异常。
DOI：
10.1128/jvi.00086-10
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发表时间：
2011
影响因子：
5.4
通讯作者：
Giam,Chou-Zen
中科院分区：
文献类型：
--
作者：
Yang,Liangpeng;Kotomura,Naoe;Ho,Yik-Khuan;Zhi,Huijun;Bixler,Sandra;Schell,MichaelJ;Giam,Chou-Zen
人类 T 淋巴细胞病毒 1 型 (HTLV-1) 是成人 T 细胞白血病/淋巴瘤 (ATL) 的病原体，ATL 是一种 CD4+T 细胞恶性肿瘤，其病因被认为与病毒反式激活因子相关。我们最近表明，Tax 可以分别通过蛋白质稳定和 mRNA 反式激活和稳定来大幅上调 p27Kip1 和 p21CIP1/WAF1 的表达。 Tax 诱导的 p21CIP1/WAF1 和 p27Kip1 激增始于 S 期，并导致细胞衰老。重要的是，被 HTLV-1 感染的 HeLa 和 SupT1 T 细胞也会停止衰老，从而挑战了 HTLV-1 感染导致细胞增殖的观点。在这里，我们使用延时显微镜来研究 Tax 对两种报告细胞系 HeLa/18x21-EGFP 和 HeLa-FUCCI 细胞周期进展的影响，这两种细胞系分别在 18 个拷贝的 Tax 响应性 21-bp 重复元件和荧光泛素细胞周期指示剂的控制下表达增强型绿色荧光蛋白 (EGFP)。表达 Tax 的 HeLa 细胞表现出延长或停滞的细胞周期阶段。其中许多绕过有丝分裂并成为单个衰老细胞，衰老相关的 β-半乳糖苷酶的表达证明了这一点。这些细胞的细胞含量是正常细胞含量的两倍，因此细胞体积增大，细胞核增大。有趣的是，诺考达唑治疗揭示了 HeLa/18x21-EGFP 细胞的一小群变异体，它们可以正常进入有丝分裂，并具有高水平的 Tax 表达，这表明防止 Tax 诱导的衰老的遗传或表观遗传变化可以以可检测的频率自发发生。
Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATL), a malignancy of CD4+T cells whose etiology is thought to be associated with the viraltrans-activator Tax. We have shown recently that Tax can drastically upregulate the expression of p27Kip1and p21CIP1/WAF1through protein stabilization and mRNAtrans-activation and stabilization, respectively. The Tax-induced surge in p21CIP1/WAF1and p27Kip1begins in S phase and results in cellular senescence. Importantly, HeLa and SupT1 T cells infected by HTLV-1 also arrest in senescence, thus challenging the notion that HTLV-1 infection causes cell proliferation. Here we use time-lapse microscopy to investigate the effect of Tax on cell cycle progression in two reporter cell lines, HeLa/18x21-EGFP and HeLa-FUCCI, that express enhanced green fluorescent protein (EGFP) under the control of 18 copies of the Tax-responsive 21-bp repeat element andfluorescentubiquitincellcycleindicators, respectively. Tax-expressing HeLa cells exhibit elongated or stalled cell cycle phases. Many of them bypass mitosis and become single senescent cells as evidenced by the expression of senescence-associated β-galactosidase. Such cells have twice the normal equivalent of cellular contents and hence are enlarged, with exaggerated nuclei. Interestingly, nocodazole treatment revealed a small variant population of HeLa/18x21-EGFP cells that could progress into mitosis normally with high levels of Tax expression, suggesting that genetic or epigenetic changes that prevent Tax-induced senescence can occur spontaneously at a detectable frequency.