p53 stabilization and functional impairment in the absence of genetic mutation or the alteration of the p14(ARF)-MDM2 loop in ex vivo and cultured adult T-cell leukemia/lymphoma cells.
p53 stabilization and functional impairment in the absence of genetic mutation or the alteration of the p14(ARF)-MDM2 loop in ex vivo and cultured adult T-cell leukemia/lymphoma cells.
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DOI：
10.1182/blood.v95.12.3939
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发表时间：
2000-06
期刊：
影响因子：
20.3
通讯作者：
S. Takemoto;R. Trovato;A. Cereseto;C. Nicot;T. Kislyakova;L. Casareto;T. Waldmann;G. Torelli;G. Franchini
中科院分区：
文献类型：
--
作者：
S. Takemoto;R. Trovato;A. Cereseto;C. Nicot;T. Kislyakova;L. Casareto;T. Waldmann;G. Torelli;G. Franchini
人T细胞嗜淋巴细胞病毒I型（HTLV-I）在体外转化T细胞，病毒反式激活因子Tax功能性地损害肿瘤抑制因子p53蛋白，其也在HTLV-I感染的T细胞中稳定。因此，p53的功能损伤对于维持病毒诱导的CD 4+成熟T细胞的增殖是必不可少的。然而，在成人T细胞白血病/淋巴瘤（ATLL）患者的CD 4+白血病细胞中，病毒反式激活因子似乎不表达，并且仅在一部分患者中发现p53突变。我们试图调查是否p53功能受损，在离体样本与ATLL患者，在基因突变的情况下。在这里，我们证明了p53蛋白也是稳定的，在离体ATLL样品（10 10研究），至少在2例p53稳定与基因突变无关。此外，ATLL细胞的电离辐射后的p53功能的评估表明，异常诱导的p53反应基因GADD 45和p21（WAF 1）在7例患者。在2例患者中，p53对细胞周期进程的调节似乎也受损。因为p53是一个调节环的一部分，也涉及MDM 2和p14（ARF），后者的蛋白质的状态也在培养或新鲜的ATLL细胞进行了评估。在建立的HTLV-I感染的T细胞系或离体ATLL细胞裂解物中，通过Western印迹分析未检测到p97 MDM 2蛋白。然而，在用特异性蛋白酶体抑制剂lactacystin处理细胞后可以容易地检测到MDM 2蛋白，这表明p53-MDM 2调节环的正常调节。类似地，p14（ARF）在离体ATLL细胞中也没有异常表达，在任何已建立的HTLV-1感染的T细胞系中也没有。因此，HTLV-I感染中的p53稳定化是在不存在基因突变和p53生理降解途径改变的情况下发生的。（血。2000;95：3939-3944）
Human T-cell lymphotropic virus type I (HTLV-I) transforms T cells in vitro, and the viral transactivator Tax functionally impairs the tumor suppressor p53 protein, which is also stabilized in HTLV-I-infected T cells. Thus, the functional impairment of p53 is essential to maintain the viral-induced proliferation of CD4+ mature T cells. However, in the CD4+ leukemic cells of patients with adult T-cell leukemia/lymphoma (ATLL), the viral transactivator does not appear to be expressed, and p53 mutations have been found only in a fraction of patients. We sought to investigate whether p53 function is impaired, in ex vivo samples from patients with ATLL, in the absence of genetic mutations. Here we demonstrate that the p53 protein is stabilized also in ex vivo ATLL samples (10 of 10 studied) and that at least in 2 patients p53 stabilization was not associated with genetic mutation. Furthermore, the assessment of p53 function after ionizing radiation of ATLL cells indicated an abnormal induction of the p53-responsive genes GADD45 and p21(WAF1) in 7 of 7 patients. In 2 of 2 patients, p53 regulation of cell-cycle progression appeared to be impaired as well. Because p53 is part of a regulatory loop that also involves MDM2 and p14(ARF), the status of the latter proteins was also assessed in cultured or fresh ATLL cells. The p97 MDM2 protein was not detected by Western blot analysis in established HTLV-I-infected T-cell lines or ex vivo ATLL cell lysates. However, the MDM2 protein could be easily detected after treatment of cells with the specific proteasome inhibitor lactacystin, suggesting a normal regulation of the p53-MDM2 regulating loop. Similarly, p14(ARF) did not appear to be aberrantly expressed in ex vivo ATLL cells nor in any of the established HTLV-I-infected T-cell lines studied. Thus, p53 stabilization in HTLV-I infection occurs in the absence of genetic mutation and alteration of the physiologic degradation pathway of p53. (Blood. 2000;95:3939-3944)