GROWTH ARREST BY INDUCTION OF P53 IN DNA DAMAGED KERATINOCYTES IS BYPASSED BY HUMAN PAPILLOMAVIRUS-16 E7

Cellular tumor suppressors p53 and Rb play an important role in contro lling cell proliferation. Inactivation of these tumor suppressor prote ins can occur by gene mutation or by association with oncoproteins fro m the small DNA tumor viruses. One function of p53 is in regulating ce ll cycle check-point control after DNA damage. To dissect the pathways by which p53 and Rb may act, the E6 and E7 oncogenes of human papillo mavirus (HBV) types 6 and 16 were introduced into primary human epithe lial cells by retroviral transfer vector, and cells were assayed for g rowth arrest after DNA damage induced by actinomycin D. The E6 or E7 o ncogenes from the low-risk HPV6 had no affect on growth arrest, p53 pr otein levels increased, Rb protein levels decreased, and Rb was predom inantly in the hypophosphorylated state similar to vector-infected cel ls. Either the E6 or the E7 oncogene from the high-risk HPV16 abrogate d growth arrest. Cells expressing HPV16 E6 (16E6) were severely reduce d in p53 protein levels that did not increase detectably after DNA dam age, Rb protein levels did not decrease, and hyperphosphorylated Rb wa s present. After DNA damage in cells expressing 16E7 p53 levels increa sed, and Rb protein levels decreased; however, Rb was predominantly in the hyperphosphorylated state. Even though p53 protein levels increas ed in response to DNA damage in cells expressing 16E7, G(1) growth arr est was bypassed. This suggests that the circuitry controlling the gro wth arrest signal after DNA damage may be interconnected between the p 53 and Rb pathways.