HUMAN T-CELL LEUKEMIA-VIRUS TYPE-I TAX ASSOCIATES WITH AND IS NEGATIVELY REGULATED BY THE NF-KAPPA-B2 P100 GENE-PRODUCT - IMPLICATIONS FOR VIRAL LATENCY
HUMAN T-CELL LEUKEMIA-VIRUS TYPE-I TAX ASSOCIATES WITH AND IS NEGATIVELY REGULATED BY THE NF-KAPPA-B2 P100 GENE-PRODUCT - IMPLICATIONS FOR VIRAL LATENCY
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DOI：
10.1128/mcb.14.2.1374
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发表时间：
1994-02-01
影响因子：
5.3
通讯作者：
GREENE, WC
中科院分区：
文献类型：
--
作者：
BERAUD, C;SUN, SC;GREENE, WC
人T细胞白血病病毒I型（HTLV-I）是成人T细胞白血病的病原，是一种由活化的人CD4 T细胞引起的侵袭性且通常致命的恶性肿瘤。HTLV-I编码一种重要的40 kda的蛋白质，称为Tax，它不仅激活这种逆转录病毒的长末端重复序列，而且还诱导一系列细胞基因。税收介导的T细胞转化可能涉及各种细胞基因的表达失调，这些基因通常通过改变各种内源性宿主转录因子的活性来调节淋巴细胞的生长。特别是，Tax能够调节各种宿主转录因子的表达或活性，包括NF-kappa B/Rel和CREB/ATF家族成员，以及细胞因子HEB-1和p67（SRF）。HTLV-I感染的另一个显著特征是存在于循环原发性白血病T细胞中的病毒潜伏期。在这项研究中，我们证明HTLV-I Tax可以在转染细胞和HTLV-I感染的白血病t细胞系中与p100 （rel相关NF-kappa B2基因的产物）物理结合。此外，Tax与p100的物理相互作用可抑制Tax诱导的HTLV-I和人类免疫缺陷病毒1型长末端重复序列的激活，这反映了p100介导的正常核表达的Tax蛋白的细胞质隔离。相反，Tax突变体选择性地不能激活细胞核NF-kappa B表达，与p100无关。总之，这些结果表明，细胞质中Tax和p100的相互作用可能在成人t细胞白血病中观察到的HTLV-I潜伏期的启动和维持中发挥重要作用。
Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of the adult T-cell leukemia, an aggressive and often fatal malignancy of activated human CD4 T cells. HTLV-I encodes an essential 40-kDa protein termed Tax that not only transactivates the long terminal repeat of this retrovirus but also induces an array of cellular genes. Tax-mediated transformation of T cells likely involves the deregulated expression of various cellular genes that normally regulate lymphocyte growth produced by altered activity of various endogenous host transcription factors. In particular, Tax is capable of modulating the expression or activity of various host transcription factors, including members of the NF-kappa B/Rel and CREB/ATF families, as well as the cellular factors HEB-1 and p67(SRF). An additional distinguishing characteristic of HTLV-I infection is the profound state of viral latency that is present in circulating primary leukemic T cells. In this study, we demonstrate that HTLV-I Tax can physically associate with p100, the product of the Rel-related NF-kappa B2 gene, both in transfected cells and in HTLV-I-infected leukemic T-cell lines. Furthermore, the physical interaction of Tax with p100 leads to the inhibition of Tax-induced activation of the HTLV-I and human immunodeficiency virus type 1 long terminal repeats, reflecting p100-mediated cytoplasmic sequestration of the normally nuclearly expressed Tax protein. In contrast, a mutant of Tax that selectively fails to activate nuclear NF-kappa B expression does not associate with p100. Together, these results suggest that the cytoplasmic interplay of Tax and p100 may play an important role in the initiation and maintenance of HTLV-I latency observed in adult T-cell leukemia.