P53-INDEPENDENT GROWTH-REGULATION OF CERVICAL-CANCER CELLS BY THE PAPILLOMAVIRUS E6 ONCOGENE

Growth of cervical carcinoma cells depends on continuous expression of high risk type human papillomavirus oncogenes E6 and E7, E6 destabili zes p53, a tumor-suppressive transcription factor, which activates exp ression of the inhibitor of cell cycle progression p21 and other genes , E6-mediated p53 degradation can therefore result in cell cycle dereg ulation, It has, however, not yet been determined whether p53 inactiva tion is sufficient to provoke cell cycle progression in established ce rvical carcinoma cells, Moreover, it has not yet been clarified whethe r E6 confers additional p53-independent growth stimuli in cancer cells , To address these questions, we analysed p53 functions in SW 756 cerv ical cancer cells in which the expression of endogenous HPV 18 E6-E7 g enes be downregulated by dexamethasone. This results significantly inc reased p53 levels and sequent cell cycle arrest in the G(1) phase, Sur prisingly, p53 activities were suppressed rather than enhanced in thes e cervical cancer cells, However, if high risk papillomavirus type 16 E6 genes, including a mutant which does not degrade p53, were expresse d in dexamethasone-treated SW 756 cells with suppressed endogenous HPV type 18 E6-E7 expression, the cells reentered the cell cycle even in the absence of a cooperating viral E7 gene, In contrast, the non oncog enic papillomavirus type 6 E6 gene did not release the cells from grow th arrest under these conditions, These data indicate that suppression of p53 functions is not sufficient to provoke cell cycle progression in E6-E7-depleted cervical cancer cells and point to a p53-independent mitotic activity to oncogenic papillomavirus type E6 genes in cervica l carcinoma cells.