p53 dysfunction precedes the activation of nuclear factor-κB during disease progression in mice expressing Tax, a human T-cell leukemia virus type 1 oncoprotein
p53 dysfunction precedes the activation of nuclear factor-κB during disease progression in mice expressing Tax, a human T-cell leukemia virus type 1 oncoprotein
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DOI：
10.1093/carcin/bgt144
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发表时间：
2013-09-01
期刊：
影响因子：
4.7
通讯作者：
Umezawa, Kazuo
中科院分区：
文献类型：
--
作者：
Ohsugi, Takeo;Ishida, Takaomi;Umezawa, Kazuo
表达Tax（一种人T细胞白血病病毒1型（HTLV-1）癌蛋白）的转基因（Tg）小鼠发生成熟的T细胞白血病/淋巴瘤。在表达Tax的Tg小鼠中的白血病细胞显示p53功能障碍和核因子-κ B（NF-κ B）活化，类似于在来自感染HTLV-1的患者的成人T细胞白血病/淋巴瘤（ATLL）细胞中观察到的。然而，目前还不清楚这些影响何时发生在HTLV-1载体在ATLL的发展。在此，我们检测了4至25月龄的Tax表达Tg（Tax-Tg）小鼠白血病发病前的p53功能和NF-κ B活性。在4-10月龄时，71%的小鼠显示p53失活，没有NF-κ B激活的证据，即使tax表达在4 - 25月龄时是一致的。DNA损伤后p53积累减少导致p53功能下降。从11月龄开始，75%的小鼠显示p53功能障碍，37.5%的小鼠显示组成性NF-κ B活化，具有p50和RelB组分。NF-κ B抑制剂脱羟甲基表氧喹诺霉素（DHMEQ）可降低NF-κ B活性（即p50/RelB），但不能恢复p53功能。在体内，用DHMEQ治疗直到24个月大防止Tax-Tg小鼠中T细胞白血病的发作。这些结果提示Tax诱导的p53功能下降可能是ATLL发病的第一阶段，而这种下降与NF-κ B B的早期激活无关。NF-κ B活性参与ATLL发作的后期阶段。
Transgenic (Tg) mice expressing Tax, a human T-cell leukemia virus type 1 (HTLV-1) oncoprotein, develop mature T-cell leukemia/lymphoma. The leukemic cells in Tg mice expressing Tax show p53 dysfunction and nuclear factor-kappa B (NF-kappa B) activation, similar to that seen in adult T-cell leukemia/lymphoma (ATLL) cells from patients infected with HTLV-1. However, it is unclear when these effects occur in HTLV-1 carriers during the development of ATLL. Here, we examined p53 function and NF-kappa B activity before the onset of leukemia in Tax-expressing Tg (Tax-Tg) mice between 4 and 25 months of age. At 4-10 months of age, 71% of mice showed p53 inactivation, without evidence for NF-kappa B activation, even though tax expression was consistent from 4 to 25 months of age. The decline in p53 function resulted from decreased p53 accumulation after DNA damage. From 11 months of age onward, 75% of mice showed p53 dysfunction and 37.5% showed constitutive NF-kappa B activation with the components of p50 and RelB. An NF-kappa B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), reduced NF-kappa B activity (i.e. p50/RelB) but did not restore p53 function. In vivo, treatment with DHMEQ until 24 months of age prevented the onset of T-cell leukemia in Tax-Tg mice. These results suggest that the Tax-induced decline in p53 function, which is independent of NF-kappa B activation in the early stage, might be the first stage in the onset of ATLL. NF-kappa B activity is involved in the later stages of ATLL onset.