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首页> 美国卫生研究院文献>Journal of Virology >Analysis of p53 Inactivation in a Human T-Cell Leukemia Virus Type 1 Tax Transgenic Mouse Model
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Analysis of p53 Inactivation in a Human T-Cell Leukemia Virus Type 1 Tax Transgenic Mouse Model

机译：人类T细胞白血病病毒1型税转基因小鼠模型中p53失活的分析。

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Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATLL). The HTLV-1 Tax protein has been strongly linked to oncogenesis and is considered to be the transforming protein of this virus. A Tax transgenic mouse model was utilized to study the contribution of p53 inactivation to Tax-mediated tumorigenesis. These mice develop primary, peripheral tumors consisting of large granular lymphocytic (LGL) cells, which also infiltrate the lymph nodes, bone marrow, spleen, liver, and lungs. Primary Tax-induced tumors and tumor-derived cell lines exhibited functional inactivation of the p53 apoptotic pathway; such tumors and tumor cell lines were resistant to an apoptosis-inducing stimulus. In contrast, p53 mutations in tumors were found to be associated with secondary organ infiltration. Three of four identified mutations inhibited transactivation and apoptosis induction activities in vitro. Furthermore, experiments which involved mating Tax transgenic mice with p53-deficient mice demonstrated minimal acceleration in initial tumor formation, but significantly accelerated disease progression and death in mice heterozygous for p53. These studies suggest that functional inactivation of p53 by HTLV-1 Tax, whether by mutation or another mechanism, is not critical for initial tumor formation, but contributes to late-stage tumor progression.
机译：1型人类T细胞白血病病毒（HTLV-1）是成人T细胞白血病/淋巴瘤（ATLL）的病原体。 HTLV-1 Tax蛋白与肿瘤发生密切相关，被认为是该病毒的转化蛋白。使用Tax转基因小鼠模型研究p53失活对Tax介导的肿瘤发生的作用。这些小鼠会发展成由大颗粒淋巴细胞（LGL）细胞组成的原发性周围肿瘤，这些细胞也会浸润淋巴结，骨髓，脾脏，肝脏和肺脏。原发性Tax诱导的肿瘤和肿瘤衍生的细胞系对p53凋亡途径具有功能性失活作用。这些肿瘤和肿瘤细胞系对诱导凋亡的刺激具有抗性。相反，发现肿瘤中的p53突变与继发器官浸润有关。四个已鉴定的突变中的三个在体外抑制反式激活和凋亡诱导活性。此外，涉及将Tax转基因小鼠与p53缺陷型小鼠交配的实验表明，初始肿瘤形成的加速最小，但p53杂合型小鼠的疾病进展和死亡显着加速。这些研究表明，无论是通过突变还是其他机制，通过HTLV-1 Tax对p53的功能失活对于最初的肿瘤形成都不是至关重要的，但有助于晚期肿瘤的发展。

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