HPV 16-E6-mediated degradation of intrinsic p53 is compensated by upregulation of p53 gene expression in normal cervical keratinocytes

Int J Oncol. 2002 Sep;21(3):561-7.

Abstract

In this study we investigated the relationship between the development of either HSILs (high-grade squamous intraepithelial lesions) or invasive cancers of the uterine cervix and the p53 codon 72 polymorphisms consisting of arginine (Arg)- or proline (Pro)-encoded allele in Japanese populations. Furthermore, we determined if intrinsic p53 is affected by the p53-degradation activities of human papillomavirus type 16 (HPV 16)-E6 in normal cervical keratinocytes with each p53 codon 72 genotype. Using PCR with p53 codon 72 polymorphic allele-specific primers, p53 genotypes of 112 normal cervical specimens and 88 cervical lesions including 44 HSILs and 44 invasive cancers were determined. The expression levels of p53 proteins and mRNAs in keratinocytes following the expression of HPV 16-E6 from an HPV 16-E6-expressing recombinant adenovirus were analyzed. The frequencies of p53 genotypes, Pro/Pro, Arg/Pro and Arg/Arg were, respectively, 12, 49 and 39% in controls; and 18, 55 and 27% in HSILs; and 11, 41 and 48% in invasive cancers. The expression levels of the p53 proteins in normal human keratinocytes of each p53 codon 72 genotype were not affected by the introduction of HPV 16-E6, whereas the p53 mRNAs were found to be upregulated regardless of the p53 genotypes when HPV 16-E6 was expressed. In statistical analysis, no relationships between p53 genotypes and the development of cervical neoplasias were found. Furthermore, we demonstrated that p53 protein expression levels in normal cervical keratinocytes is not affected by the p53-degradation activities of HPV E6, probably due to a tight transcriptional regulation of p53.

MeSH terms

  • Cervix Uteri / cytology
  • Cervix Uteri / metabolism*
  • Cervix Uteri / physiology
  • Cervix Uteri / virology
  • Female
  • Genes, p53 / genetics*
  • Humans
  • Keratinocytes / metabolism*
  • Keratinocytes / physiology
  • Keratinocytes / virology
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / metabolism*
  • Papillomaviridae / genetics
  • Polymerase Chain Reaction
  • Polymorphism, Genetic
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Repressor Proteins*
  • Tumor Suppressor Protein p53 / biosynthesis
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Up-Regulation
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / virology

Substances

  • E6 protein, Human papillomavirus type 16
  • Oncogene Proteins, Viral
  • RNA, Messenger
  • Repressor Proteins
  • Tumor Suppressor Protein p53