Bmi-1 cooperates with human papillomavirus type 16 E6 to immortalize normal human oral keratinocytes

Exp Cell Res. 2007 Feb 1;313(3):462-72. doi: 10.1016/j.yexcr.2006.10.025. Epub 2006 Oct 28.


Bmi-1 is a member of the polycomb group (PcG) transcription repressors and is implicated in human carcinogenesis. In normal human oral keratinocytes (NHOK), we found that exogenous Bmi-1 expression significantly extended the replicative life span without causing cellular immortalization. Immortalization of NHOK occurs only in combination with human papillomavirus type 16 E6 (HPV-16 E6) but not with E7. During immortalization of NHOK by sequential expression of exogenous Bmi-1 and E6, telomerase activation was observed only after the cells had overcome crisis. Genetic analysis with E6 deletion mutants revealed that the intact second zinc finger domain (amino acids 118-122) was necessary for its cooperative effects with Bmi-1 in the immortalization process. Using these mutants, we found that the increased telomerase activity was closely associated with cell immortalization by Bmi-1 and E6, whereas p53 degradation was not. Using microarray analysis, we identified genes that are immortalization-specific and may participate in the process of NHOK immortalization by Bmi-1 and HPV-16 E6. Our results provide new information on the roles of Bmi-1 and HPV-16 E6 in the multi-step process of oral epithelial carcinogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism
  • Cell Transformation, Viral*
  • Cells, Cultured
  • Enzyme Activation
  • Gene Expression Regulation
  • Humans
  • Keratinocytes / metabolism
  • Keratinocytes / physiology*
  • Mouth / metabolism
  • Mouth / physiology*
  • Nuclear Proteins / metabolism*
  • Nuclear Proteins / physiology
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / metabolism
  • Oncogene Proteins, Viral / physiology*
  • Papillomavirus E7 Proteins
  • Polycomb Repressive Complex 1
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins / physiology
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Repressor Proteins / physiology*
  • Sequence Deletion
  • Telomerase / metabolism
  • Transduction, Genetic
  • Tumor Suppressor Protein p53 / metabolism
  • Zinc Fingers


  • BMI1 protein, human
  • E6 protein, Human papillomavirus type 16
  • Nuclear Proteins
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • Tumor Suppressor Protein p53
  • oncogene protein E7, Human papillomavirus type 16
  • Polycomb Repressive Complex 1
  • Telomerase