INHIBITION OF CERVICAL-CARCINOMA CELL-LINE PROLIFERATION BY THE INTRODUCTION OF A BOVINE PAPILLOMAVIRUS REGULATORY GENE

Human papillomavirus (HPV) E6 and E7 oncogenes are expressed in the gr eat majority of human cervical carcinomas, whereas the viral E2 regula tory gene is usually disrupted in these cancers. To investigate the ro les of the papillomavirus E2 genes in the development and maintenance of cervical carcinoma, the bovine papillomavirus (BPV) E2 gene was acu tely introduced into cervical carcinoma cell lines by infection with h igh-titer stocks of simian virus 40-based recombinant viruses. Express ion of the BFV E2 protein in HeLa, C-4I, and MS751 cells results in sp ecific inhibition of the expression of the resident HPV type 18 (HPV18 ) E6 and E7 genes and in inhibition of cell growth. HeLa cells, in whi ch HPV gene expression is nearly completely abolished, undergo a drama tic 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 a ccompanied by a marked increase in the level of the cellular p53 tumor suppressor protein, apparently as a consequence of abrogation of HPV1 8 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 li nes that do not contain HPV DNA are not inhibited. Thus, a number of c ervical carcinoma cell lines are remarkably sensitive to growth inhibi tion by the E2 protein. Although BPV E2-mediated inhibition of HPV18 E 6 and E7 expression may contribute to growth inhibition in some of the cervical carcinoma cell lines, the BPV E2 protein also appears to exe rt a growth-inhibitory effect that is independent of its effects on HP V gene expression.