Efficiency of binding the retinoblastoma protein correlates with the transforming capacity of the E7 oncoproteins of the human papillomaviruses.
The human papillomaviruses (HPVs) associated with genital tract lesions can be classified as either "high risk" or "low risk" based on their association with human anogenital cancer. The E7 proteins of the high-risk and the low-risk viruses are quite similar in their amino acid composition and structural organization yet differ in their transforming potential and in a number of biochemical properties. A series of chimeric proteins consisting of segments of the high-risk HPV-16 and the low-risk HPV-6 E7 proteins were constructed in order to define which domains within the amino-terminal half of E7 were responsible for the different biological and biochemical properties. The E7 oncogenic capacity, which was determined by assaying transformation of baby rat kidney cells in cooperation with an activated ras oncogene, segregated with the retinoblastoma tumor suppressor protein (pRB) binding domain of the HPV-16 E7 protein. A comparison of the pRB binding sites of the sequenced genital tract HPVs revealed a consistent amino acid difference (aspartic acid/glycine) between the high-risk and low-risk viruses. Single amino acid substitution mutations were generated at this position in the HPV-6 and HPV-16 E7 proteins, and this single amino acid residue was shown to be the principal determinant responsible for the differences in the apparent pRB binding affinity and transformation capacity distinguishing the HPV E7 proteins of the high-risk and low-risk HPVs.
Heck
D V
DV
Laboratory of Tumor Virus Biology, National Cancer Institute, Bethesda, MD 20892.
Yee
C L
CL
Howley
P M
PM
Münger
K
K
D017456:Adenovirus Early Proteins; D000260:Adenoviruses, Human / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000235:genetics; D005814:Genes, Viral; D011905:Genes, ras; D006801:Humans; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000378:metabolism; D027383:Papillomaviridae / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D011485:Protein Binding; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism*; D012689:Sequence Homology, Nucleic Acid; D014162:Transfection
D017456:Adenovirus Early Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; C059731:oncogene protein E7, Human papillomavirus type 16; C062495:oncogene protein E7, Human papillomavirus type 6; D015500:Chloramphenicol O-Acetyltransferase