Cellular proteins involved in papillomavirus-induced transformation.
Human papillomaviruses (HPVs) are associated with at least 80% of cervical carcinomas and are classified as high-risk or low-risk based on whether or not they are commonly found in cervical cancers. The high-risk HPVs have early gene products (E6 and E7) that immortalize human keratinocytes and are at least partially responsible for causing cervical carcinoma. E6 and E7 from the high-risk viruses interact strongly with the tumor suppressors p53 and Rb; those from the low-risk HPVs do not. Transformation involves a multi-step process and requires additional factors besides high-risk HPV infection. High-risk HPVs are capable of immortalizing primary human keratinocytes in tissue culture, but such cells become transformed only after certain chromosomal changes take place, possibly having to do with oncogene activation. The DNA of high-risk HPVs is frequently (if not always) integrated into the genome of cancer cells; it is normally episomal in premalignant lesions. Integration disrupts the E2 and E5 genes and viral gene regulation. Cells containing integrated viral DNA show excessively high levels of E6 and E7. While there is some conflicting evidence, it appears that the p53 and Rb tumor-suppressor genes are more frequently mutated in HPV-negative tumors than they are in HPV-positive tumors, suggesting that for tumor formation to proceed the p53 and Rb proteins must be inactivated either by interaction with the viral proteins or by mutation. The presence of an activated oncogene in a cell lacking functional p53 or Rb may then be sufficient to cause tumor progression.
Swan
D C
DC
National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.
Vernon
S D
SD
Icenogle
J P
JP
D001483:Base Sequence; D002472:Cell Transformation, Viral; D004247:DNA; D016147:Genes, Tumor Suppressor; D006801:Humans; D008969:Molecular Sequence Data; D009857:Oncogenes; D027383:Papillomaviridae / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology; D014764:Viral Proteins / Q000502:physiology
D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; D014764:Viral Proteins; D004247:DNA