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

T. D. Kessis, R. J. Slebos, W. G. Nelson, M. B. Kastan, B. S. Plunkett, S. M. Han, A. T. Lorincz, L. Hedrick, K. R. Cho

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3988-3992
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume90
Issue number9
DOIs
StatePublished - Jan 1 1993

Keywords

  • DNA replication
  • carcinogenesis
  • cell cycle
  • cervical carcinoma

ASJC Scopus subject areas

  • General

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