Human papillomavirus 16 E6 expression disrupts the p53-mediated cellular response to DNA damage.

Kessis TD, Slebos RJ, Nelson WG, Kastan MB, Plunkett BS, Han SM, Lorincz AT, Hedrick L, Cho KR
Proc Natl Acad Sci U S A. 1993 90 (9): 3988-92

PMID: 8387205 · PMCID: PMC46431 · DOI:10.1073/pnas.90.9.3988

Infection with certain types of human papillomaviruses (HPV) is highly associated with carcinomas of the human uterine cervix. However, HPV infection alone does not appear to be sufficient for the process of malignant transformation, suggesting the requirement of additional cellular events. After DNA damage, normal mammalian cells exhibit G1 cell-cycle arrest and inhibition of replicative DNA synthesis. This mechanism, which requires wild-type p53, presumably allows cells to undertake DNA repair and avoid the fixation of mutations. We directly tested whether the normal response of cervical epithelial cells to DNA damage may be undermined by interactions between the E6 protein expressed by oncogenic HPV types and wild-type p53. We treated primary keratinocytes with the DNA-damaging agent actinomycin D and demonstrated inhibition of replicative DNA synthesis and a significant increase in p53 protein levels. In contrast, inhibition of DNA synthesis and increases in p53 protein did not occur after actinomycin D treatment of keratinocytes immortalized with HPV16 E6/E7 or in cervical carcinoma cell lines containing HPV16, HPV18, or mutant p53 alone. To test the effects of E6 alone on the cellular response to DNA damage, HPV16 E6 was expressed in the carcinoma cell line RKO, resulting in undetectable baseline levels of p53 protein and loss of the G1 arrest that normally occurs in these cells after DNA damage. These findings demonstrate that oncogenic E6 can disrupt an important cellular response to DNA damage mediated by p53 and may contribute to the subsequent accumulation of genetic changes associated with cervical tumorigenesis.

MeSH Terms (28)

Cell Cycle Cells, Cultured Cervix Uteri Dactinomycin DNA, Viral DNA Damage DNA Replication Epithelial Cells Epithelium Female G1 Phase Genes, p53 HeLa Cells Humans Keratinocytes Male Oncogene Proteins, Viral Open Reading Frames Papillomaviridae Polymerase Chain Reaction Repressor Proteins Restriction Mapping RNA, Messenger RNA, Viral Transfection Tumor Cells, Cultured Tumor Suppressor Protein p53 Uterine Cervical Neoplasms

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