Human papillomavirus type 16 E7 protein sensitizes cervical keratinocytes to apoptosis and release of interleukin-1alpha

Oncogene. 1998 Sep 10;17(10):1195-205. doi: 10.1038/sj.onc.1202054.

Abstract

Interleukin-1alpha (IL-1alpha) is a multifunctional cytokine that promotes inflammation, tissue remodeling and epithelial hyperplasia. Keratinocytes produce and sequester large amounts of biologically active IL-1alpha which can be released after injury or infection. We show that high level expression of human papillomavirus (HPV) type 16 E6 and E7 oncoproteins enhanced release of IL-1alpha from cultures of normal cervical keratinocytes (relative effectiveness E7 > E6/E7 >> E6 > control). The amount of IL-1alpha released was directly related to the ability of E7 or E6/E7 to stimulate apoptosis. E7 proteins that bound the retinoblastoma protein (Rb) strongly (HPV-16 and -18) induced more IL-1alpha release than those that bound poorly (HPV-6 and an HPV-16 E7 24gly mutant). Furthermore, overexpression of the E2F-1 transcription factor, a downstream target of Rb, induced extensive apoptosis and IL-1alpha release. Apoptosis and IL-1alpha release in response to growth factor removal occurred in part through a p53-independent pathway as coexpression of E6 and downregulation of p53 did not prevent either response. Immunohistochemical analyses showed that IL-1alpha was expressed by keratinocytes in normal cervical epithelia, low and high grade dysplasias, and cervical carcinomas. However, HPV-16 E6/E7 RNA expression and apoptosis increased in parallel in proliferating keratinocytes in severe dysplasias and carcinomas suggesting that IL-1alpha release is associated with progression to high grade disease. Thus, high level expression of the HPV-16 E7 protein sensitizes keratinocytes to apoptosis which results in release of IL-1alpha.

MeSH terms

  • Apoptosis / genetics*
  • Carrier Proteins*
  • Cell Cycle Proteins*
  • Cells, Cultured
  • Cervix Uteri / cytology*
  • Cervix Uteri / virology
  • Cytokines / metabolism
  • DNA-Binding Proteins*
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • Female
  • Gene Expression Regulation
  • Humans
  • Interleukin-1 / genetics
  • Interleukin-1 / metabolism*
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Keratinocytes / virology*
  • Oncogene Proteins, Viral / genetics*
  • Oncogene Proteins, Viral / pharmacology
  • Papillomavirus E7 Proteins
  • Repressor Proteins*
  • Retinoblastoma-Binding Protein 1
  • Transcription Factor DP1
  • Transcription Factors / metabolism
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / virology

Substances

  • Carrier Proteins
  • Cell Cycle Proteins
  • Cytokines
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • E6 protein, Human papillomavirus type 16
  • Interleukin-1
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Repressor Proteins
  • Retinoblastoma-Binding Protein 1
  • Transcription Factor DP1
  • Transcription Factors
  • oncogene protein E7, Human papillomavirus type 16