Hwang E S, Riese D J, Settleman J, Nilson L A, Honig J, Flynn S, DiMaio D
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510-8005.
J Virol. 1993 Jul;67(7):3720-9. doi: 10.1128/JVI.67.7.3720-3729.1993.
Human papillomavirus (HPV) E6 and E7 oncogenes are expressed in the great majority of human cervical carcinomas, whereas the viral E2 regulatory gene is usually disrupted in these cancers. To investigate the roles of the papillomavirus E2 genes in the development and maintenance of cervical carcinoma, the bovine papillomavirus (BPV) E2 gene was acutely introduced into cervical carcinoma cell lines by infection with high-titer stocks of simian virus 40-based recombinant viruses. Expression of the BPV E2 protein in HeLa, C-4I, and MS751 cells results in specific inhibition of the expression of the resident HPV type 18 (HPV18) E6 and E7 genes and in inhibition of cell growth. HeLa cells, in which HPV gene expression is nearly completely abolished, undergo a dramatic and rapid inhibition of proliferation, which appears to be largely a consequence of a block in progression from the G1 to the S phase of the cell cycle. Loss of HPV18 gene expression in HeLa cells is also accompanied by a marked increase in the level of the cellular p53 tumor suppressor protein, apparently as a consequence of abrogation of HPV18 E6-mediated destabilization of p53. The proliferation of HT-3 cells, a human cervical carcinoma cell line devoid of detectable HPV DNA, is also inhibited by E2 expression, whereas two other epithelial cell lines that do not contain HPV DNA are not inhibited. Thus, a number of cervical carcinoma cell lines are remarkably sensitive to growth inhibition by the E2 protein. Although BPV E2-mediated inhibition of HPV18 E6 and E7 expression may contribute to growth inhibition in some of the cervical carcinoma cell lines, the BPV E2 protein also appears to exert a growth-inhibitory effect that is independent of its effects on HPV gene expression.
人乳头瘤病毒（HPV）的E6和E7癌基因在绝大多数人类宫颈癌中均有表达，而病毒E2调控基因在这些癌症中通常遭到破坏。为了研究乳头瘤病毒E2基因在宫颈癌发生和维持过程中的作用，通过用高滴度的基于猿猴病毒40的重组病毒株感染，将牛乳头瘤病毒（BPV）E2基因急性导入宫颈癌细胞系。BPV E2蛋白在HeLa、C-4I和MS751细胞中的表达导致内源性18型HPV（HPV18）E6和E7基因表达受到特异性抑制，并抑制细胞生长。HPV基因表达几乎完全被消除的HeLa细胞，其增殖受到显著且快速的抑制，这似乎主要是细胞周期从G1期进入S期受阻的结果。HeLa细胞中HPV18基因表达的缺失还伴随着细胞p53肿瘤抑制蛋白水平的显著升高，这显然是由于HPV18 E6介导的p53去稳定作用被消除所致。HT-3细胞是一种未检测到HPV DNA的人类宫颈癌细胞系，其增殖也受到E2表达的抑制，而另外两个不含HPV DNA的上皮细胞系则未受抑制。因此，许多宫颈癌细胞系对E2蛋白介导的生长抑制非常敏感。尽管BPV E2介导的对HPV18 E6和E7表达的抑制可能在某些宫颈癌细胞系的生长抑制中起作用，但BPV E2蛋白似乎也发挥了一种与其对HPV基因表达的影响无关的生长抑制作用。
