Human immunodeficiency virus type 1 tat increases the expression of cleavage and polyadenylation specificity factor 73-kilodalton subunit modulating cellular and viral expression
Human immunodeficiency virus type 1 tat increases the expression of cleavage and polyadenylation specificity factor 73-kilodalton subunit modulating cellular and viral expression
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DOI：
10.1128/jvi.78.13.6846-6854.2004
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发表时间：
2004-07-01
影响因子：
5.4
通讯作者：
Muñoz, E
中科院分区：
文献类型：
--
作者：
Calzado, MA;Sancho, R;Muñoz, E
人类免疫缺陷病毒1型(HIV-1)Tat蛋白是HIV基因表达和病毒复制所必需的，它对多种细胞功能具有多效性。例如，TAT蛋白能够调节宿主细胞基因的转录速度，并与信号机制相互作用，导致细胞功能障碍。为了研究HIV-1Tat对宿主细胞的影响，我们利用差异显示的方法鉴定了Tat表达细胞系中上调或下调的几个基因。HIV-1 Tat特异性地增加切割和多聚腺苷酸化特异性因子(CPSF)73 kDa亚基(CPSF3)的表达，而不影响CPSF复合体的160 kDa和100 kDa亚基的表达。该复合体由四个亚基组成，通过与其他因子的协调作用，在前mRNAs的3‘端处理中发挥关键作用。CPSF3过表达实验和通过mRNA干扰抑制内源性CPSF3的实验表明，该复合体的这个亚单位是病毒和细胞基因表达的重要调节蛋白。除了已知的CPSF3在RNA多腺化中的作用外，我们还发现该蛋白通过抑制MDM2基因启动子而发挥转录活性。因此，HIV-1-TAT上调CPSF3可能代表了一种新的机制，通过这种机制，这种病毒增加了mRNA的处理，导致细胞和病毒基因表达的增加。
The human immunodeficiency virus type 1 (HIV-1) Tat protein, which is essential for HIV gene expression and viral replication, is known to mediate pleiotropic effects on various cell functions. For instance, Tat protein is able to regulate the rate of transcription of host cellular genes and to interact with the signaling machinery, leading to cellular dysfunction. To study the effect that HIV-1 Tat exerts on the host cell, we identified several genes that were up- or down-regulated in tat-expressing cell lines by using the differential display method. HIV-1 Tat specifically increases the expression of the cleavage and polyadenylation specificity factor (CPSF) 73-kDa subunit (CPSF3) without affecting the expression of the 160- and 100-kDa subunits of the CPSF complex. This complex comprises four subunits and has a key function in the 3'-end processing of pre-mRNAs by a coordinated interaction with other factors. CPSF3 overexpression experiments and knockdown of the endogenous CPSF3 by mRNA interference have shown that this subunit of the complex is an important regulatory protein for both viral and cellular gene expression. In addition to the known CPSF3 function in RNA polyadenylation, we also present evidence that this protein exerts transcriptional activities by repressing the mdm2 gene promoter. Thus, HIV-1-Tat up-regulation of CPSF3 could represent a novel mechanism by which this virus increases mRNA processing, causing an increase in both cell and viral gene expression.