Massimi P, Banks L
International Centre for Genetic Engineering and Biotechnology, Padriciano 99, Trieste, I-34012, Italy.
Virology. 1997 Jan 6;227(1):255-9. doi: 10.1006/viro.1996.8315.
The major transforming protein of human papillomaviruses (HPVs) is encoded by the E7 gene. This protein cooperates with activated oncogenes to transform primary rodent cells and with the viral E6 gene to immortalize primary human keratinocytes. Numerous cellular targets of HPV E7 have now been identified including pRb, p107, cyclin A, TATA box binding protein (TBP), and members of the AP-1 transcription factor family. As with Adenovirus E1a, many of these interactions are important for the ability of E7 to transform cells. Recent studies have demonstrated that Adenovirus E1a can also inhibit the transcriptional activity of the cellular tumor suppressor protein, p53. We have performed a series of analyses to determine whether HPV E7 proteins share this characteristic. We show that HPV E7 proteins derived from both benign and tumor-associated HPV types are able to inhibit p53 transcriptional activity. Mutational analysis of the HPV-16 E7 protein reveals that a key domain involved in mediating this activity is the casein kinase II (CKII) recognition site, which has been shown to modulate E7 binding to TBP. We further show that E7 does not bind to p53 directly, but will do so in the presence of exogenously added TBP and that this binding is increased following CKII phosphorylation. These results suggest that the E7-TBP interaction may be responsible for inhibiting p53 transcriptional activity.
人乳头瘤病毒（HPV）的主要转化蛋白由E7基因编码。该蛋白与激活的癌基因协同作用转化原代啮齿动物细胞，并与病毒E6基因协同作用使原代人角质形成细胞永生化。目前已鉴定出HPV E7的众多细胞靶点，包括pRb、p107、细胞周期蛋白A、TATA盒结合蛋白（TBP）以及AP-1转录因子家族成员。与腺病毒E1a一样，这些相互作用中的许多对于E7转化细胞的能力很重要。最近的研究表明，腺病毒E1a还可抑制细胞肿瘤抑制蛋白p53的转录活性。我们进行了一系列分析以确定HPV E7蛋白是否具有这一特性。我们发现，源自良性和肿瘤相关HPV类型的HPV E7蛋白均能够抑制p53的转录活性。对HPV-16 E7蛋白的突变分析表明，介导该活性的关键结构域是酪蛋白激酶II（CKII）识别位点，该位点已被证明可调节E7与TBP的结合。我们进一步表明，E7不直接与p53结合，但在外源添加TBP的情况下会结合，并且这种结合在CKII磷酸化后会增加。这些结果表明，E7-TBP相互作用可能是抑制p53转录活性的原因。
