THE TUMOR-SUPPRESSOR PROTEIN P53 STRONGLY ALTERS HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REPLICATION
THE TUMOR-SUPPRESSOR PROTEIN P53 STRONGLY ALTERS HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REPLICATION
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DOI：
10.1128/jvi.68.7.4302-4313.1994
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发表时间：
1994-07-01
影响因子：
5.4
通讯作者：
POMERANTZ, RJ
中科院分区：
文献类型：
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作者：
DUAN, LX;OZAKI, I;POMERANTZ, RJ
p53 肿瘤抑制基因产物是一种序列特异性 DNA 结合蛋白，已被证明在体外和体内均可充当转录激活剂和阻遏剂。最近观察到，p53 的 N 端酸性结构域直接与通用转录因子 TF IID 的 TATA 盒结合蛋白亚基结合，与其在转录调节中的作用一致。现在已证明，在共转染测定系统中，野生型 p53 (wt-p53) 可抑制人类免疫缺陷病毒 1 型 (HIV-1) 长末端重复 (LTR) 导向的氯霉素乙酰转移酶活性。重要的是，体外转录测定也证明了 wt-p53 对 HIV-1 LTR 的这种影响。此外，HIV-1 LTR 的 Spl 位点和 TATA 盒被证明是参与 p53 对该病毒启动子诱导作用的主要位点。 HIV-1 LTR 的上游元件，包括核因子 kappa B (NF-KB) 结合位点，可降低 p53 诱导的病毒转录抑制作用。当 HIV-1 TAR 序列和 Tat 蛋白存在时，HIV-1 LTR 对 wt-p53 诱导的抑制也变得不太敏感。通过使用逆转录病毒载体传递系统，p53 基因的突变形式在两种 HIV-1 潜伏感染细胞系 ACH-2 和 U1 中表达。在 ACH-2 细胞系中，现已证明含有 p53 的内源突变形式（氨基酸 248，Arg 至 Gln），额外的突变 p53 蛋白不会改变 HIV-1 的复制。在完全缺乏内源性 p53 的 U1 细胞中，突变体 p53 的过度表达导致 HIV-1 复制增加。因此，这些数据表明wt-p53和突变p53蛋白在控制HIV-1复制模式和前病毒潜伏期中可能发挥功能作用。
The p53 tumor suppressor gene product, a sequence-specific DNA-binding protein, has been shown to act as a transcriptional activator and repressor both in vitro and in vivo. Consistent with its role in regulating transcription are recent observations that the N-terminal acidic domain of p53 binds directly to the TATA box-binding protein subunit of the general transcription factor, TF IID. It is now demonstrated that wild-type p53 (wt-p53) inhibits human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR)-directed chloramphenicol acetyltransferase activity in a cotransfection assay system. Importantly, this effect of wt-p53 on the HIV-1 LTR was also demonstrated by in vitro transcription assays. In addition, the Spl sites and the TATA box of the HIV-1 LTR are demonstrated to be the primary sites involved with p53-induced effects on this viral promoter. The upstream elements of the HIV-1 LTR, including the nuclear factor kappa B (NF-KB) binding sites, decrease the p53-induced inhibitory effects on viral transcription. In the presence of the HIV-1 TAR sequence and Tat protein, the HIV-1 LTR also becomes less sensitive to wt-p53-induced inhibition. By using a retroviral vector delivery system, mutant forms of p53 genes were expressed in two HIV-1 latently infected cell lines, ACH-2 and U1. In the ACH-2 cell line, which is now demonstrated to contain an endogenous mutant form of p53 (amino acid 248, Arg to Gln), additional mutant p53 proteins did not alter HIV-1 replication. In U1 cells, which completely lack endogenous p53, overexpression of mutant p53 led to an increase in HIV-1 replication. Thus, these data indicate a possible functional role far wt-p53 and mutant p53 proteins in the control of HIV-1 replication patterns and proviral latency.