ABROGATION OF GROWTH ARREST SIGNALS BY HUMAN PAPILLOMAVIRUS TYPE-16 E7 IS MEDIATED BY SEQUENCES REQUIRED FOR TRANSFORMATION

Cells arrest in the G(1) or G(0) phase of the cell cycle in response t o a variety of negative growth signals that induce arrest hy different molecular pathways. The ability of human papillomavirus (HPV) oncogen es to bypass these signals and allow cells to progress into the S phas e probably contributes to the neoplastic potential of the virus. The E 7 protein of HPV-16 was able to disrupt the response of epithelial cel ls to three different negative growth arrest signals: quiescence impos ed upon suprabasal epithelial cells, G(1) arrest induced by DNA damage , and inhibition of DNA synthesis caused by treatment with transformin g growth factor beta. The same set of mutated E7 proteins was able to abrogate all three growth arrest signals. Mutant proteins that failed to abrogate growth arrest signals were transformation deficient and in cluded E7 proteins that bound retinoblastoma protein in vitro. In cont rast, HPV-16 E6 was able to bypass only DNA damage-induced G(1) arrest , not suprabasal quiescence or transforming growth factor beta-induced arrest. The E6 and E7 proteins from the low-risk virus HPV-6 were not able to bypass any of the growth arrest signals.