Binding of high-risk human papillomavirus E6 oncoproteins to the human homologue of the Drosophila discs large tumor suppressor protein.
In the majority of cervical cancers, DNAs of high-risk mucosotpropic human papillomaviruses (HPVs), such as type 16, are maintained so as to express two viral proteins, E6 and E7, suggesting an essential importance to carcinogenesis. The high-risk HPV E6 proteins are known to inactivate p53 tumor suppressor protein but appear to have an additional, molecularly unknown function(s). In this study, we demonstrate that these E6 proteins can bind to the second PDZ domain of the human homologue of the Drosophila discs large tumor suppressor protein (hDLG) through their C-terminal XS/TXV/L (where X represents any amino acid, S/T serine or threonine, and V/L valine or leucine) motif. This finding is similar to the interaction between the adenomatous polyposis coli gene product and hDLG. E6 mutants losing the ability to bind to hDLG are no longer able to induce E6-dependent transformation of rodent cells. These results suggest an intriguing possibility that interaction between the E6 protein and hDLG or other PDZ domain-containing proteins could be an underlying mechanism in the development of HPV-associated cancers.
Kiyono
T
T
Laboratory of Viral Oncology, Aichi Cancer Center, Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464, Japan.
Hiraiwa
A
A
Fujita
M
M
Hayashi
Y
Y
Akiyama
T
T
Ishibashi
M
M
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001940:Breast; D019556:COS Cells; D002460:Cell Line; D017124:Conserved Sequence; D000074288:Discs Large Homolog 1 Protein; D004330:Drosophila; D029721:Drosophila Proteins; D004848:Epithelium; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D019476:Insect Proteins / Q000737:chemistry; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000378:metabolism*; D027383:Papillomaviridae; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012097:Repressor Proteins; D012307:Risk Factors; D016415:Sequence Alignment; D014162:Transfection; D025521:Tumor Suppressor Proteins; D002583:Uterine Cervical Neoplasms / Q000821:virology
D048868:Adaptor Proteins, Signal Transducing; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; D029721:Drosophila Proteins; C068651:E6 protein, Human papillomavirus type 16; D019476:Insect Proteins; D008565:Membrane Proteins; D009856:Oncogene Proteins, Viral; D011506:Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C070350:dlg1 protein, Drosophila