Role of the retinoblastoma pathway in senescence triggered by repression of the human papillomavirus E7 protein in cervical carcinoma cells

Cancer Res. 2004 May 1;64(9):3079-86. doi: 10.1158/0008-5472.can-03-3739.


Repression of the endogenous human papillomavirus (HPV) type 18 E7 gene in HeLa cervical carcinoma cells by the bovine papillomavirus E2 transcription factor activates the retinoblastoma (Rb) pathway and induces cells to undergo senescence. To determine whether activation of the Rb pathway is responsible for senescence in response to HPV18 E7 repression, we tested the ability of wild-type and mutant E7 proteins to affect the activity of the Rb pathway and to modulate senescence in these cells. Enforced expression of the wild-type HPV16 E7 protein prevented Rb activation in response to E2 expression and impaired senescence. Importantly, there was an absolute correlation between the ability of mutant E7 proteins to inactivate the Rb pathway and to inhibit senescence in HeLa cells. Similar results were obtained in HT-3 cervical carcinoma cells. These results provide strong genetic evidence that activation of the Rb pathway is required for senescence in response to E7 repression. Hence, continuous neutralization of the Rb pathway by the E7 protein is required to maintain the proliferation of cervical carcinoma cells. Similarly, our results indicate that activation of the Rb pathway can prevent apoptosis induced by repression of the HPV18 E6 gene in HeLa cells.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenovirus E1A Proteins / biosynthesis
  • Adenovirus E1A Proteins / genetics
  • Adenovirus E1A Proteins / physiology
  • Cellular Senescence / genetics
  • Cellular Senescence / physiology*
  • DNA-Binding Proteins*
  • Female
  • Gene Expression Regulation, Neoplastic
  • HeLa Cells
  • Humans
  • Mutation
  • Oncogene Proteins, Viral / antagonists & inhibitors*
  • Oncogene Proteins, Viral / biosynthesis
  • Oncogene Proteins, Viral / genetics
  • Papillomaviridae / genetics
  • Papillomaviridae / metabolism
  • Papillomavirus E7 Proteins
  • Repressor Proteins*
  • Retinoblastoma Protein / deficiency
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / physiology*
  • Signal Transduction / physiology
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology*
  • Uterine Cervical Neoplasms / virology*


  • Adenovirus E1A Proteins
  • DNA-Binding Proteins
  • E6 protein, Human papillomavirus type 16
  • E7 protein, Human papillomavirus type 18
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Repressor Proteins
  • Retinoblastoma Protein
  • oncogene protein E7, Human papillomavirus type 16