The early HPV16 proteins can regulate mRNA levels of cell cycle genes in human cervical carcinoma cells by p53-independent mechanisms

Abstract

Cervical carcinoma-associated human papillomavirus type 16 (HPV16) encodes E6 and E7 oncoproteins which inactivate p53 and Rb, respectively, but these interactions are not sufficient to account for the oncogenic potential of the virus. Several viral promoters were shown to be regulated by E6 and E7. To identify genes as cellular targets of the HPV16 early proteins, we transfected a new HPV-negative and p53-mutated cervical carcinoma-derived cell line with either the HPV16 full-length genome or the HPV16 E6 gene. HPV16 clones but not 16E6 clones showed a decreased doubling time that was not related to the viral DNA and mRNA patterns. In exponentially growing cells as well as in cells synchronized by serum starvation, expression of the E6 gene was associated with upregulation of the c-fos and c-jun proto- oncogenes and with downregulation of the c-Ha-ras gene. Furthermore, a viral gene other than E6 may be involved in downregulation of p53 because a reduced mRNA level at the G1/S transition was observed only in HPV16-cells. The present study on natural host cells indicates p53-independent transcriptional modulations of cell cycle regulatory genes related to HPV16 E6 and E7 expression.