Bmi-1 cooperates with human papillomavirus type 16 E6 to immortalize normal human oral keratinocytes.
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.
Kim
Reuben H
RH
School of Dentistry at UCLA, Los Angeles, CA 90095, USA.
Kang
Mo K
MK
Shin
Ki-Hyuk
KH
Oo
Zin M
ZM
Han
Thomas
T
Baluda
Marcel A
MA
Park
No-Hee
NH
D000375:Aging / Q000378:metabolism; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000502:physiology*; D009055:Mouth / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism* / Q000502:physiology; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050725:Papillomavirus E7 Proteins; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000378:metabolism* / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D017384:Sequence Deletion; D019098:Telomerase / Q000378:metabolism; D014161:Transduction, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D016335:Zinc Fingers
C069077:BMI1 protein, human; C068651:E6 protein, Human papillomavirus type 16; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C059731:oncogene protein E7, Human papillomavirus type 16; D063150:Polycomb Repressive Complex 1; D019098:Telomerase