Interactions of HPV E6 and E7 oncoproteins with tumour suppressor gene products.
The HPVs associated with anogenital cancers encode two oncoproteins, E6 and E7. Both E6 and E7 can form specific complexes with tumour suppressor gene products. The E7 protein binds to the retinoblastoma tumour suppressor gene product pRB, with a preference for the underphosphorylated, "active" form of pRB. The E7 proteins derived from the "high risk" HPVs bind to pRB with a higher affinity than the E7 proteins from the "low risk" HPVs. The "high risk" HPV E6 proteins can associate with the p53 tumour suppressor protein. This interaction promotes the degradation of p53 in vitro, which presumably accounts for the very low levels of p53 in cervical carcinoma cell lines. The functional inactivation of pRB and p53 by the HPV oncoproteins E7 and E6, respectively, are likely to be important steps in cervical carcinogenesis, since mutations in the RB and p53 genes were detected in HPV negative but not HPV positive cervical carcinoma cell lines. Cytogenetic studies strongly suggest, however, that additional chromosomal changes may be necessary for carcinogenic progression of HPV induced anogenital lesions.
Münger
K
K
Laboratory of Tumour Virus Biology, National Cancer Institute, Bethesda, Maryland 20892.
Scheffner
M
M
Huibregtse
J M
JM
Howley
P M
PM
D004279:DNA, Viral / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D027383:Papillomaviridae / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014412:Tumor Virus Infections / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics
D004279:DNA, Viral; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53