Binding of high-risk human papillomavirus E6 oncoproteins to the human homologue of the Drosophila discs large tumor suppressor protein
Binding of high-risk human papillomavirus E6 oncoproteins to the human homologue of the Drosophila discs large tumor suppressor protein
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DOI：
10.1073/pnas.94.21.11612
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发表时间：
1997-10-14
影响因子：
11.1
通讯作者：
Ishibashi, M
中科院分区：
文献类型：
--
作者：
Kiyono, T;Hiraiwa, A;Ishibashi, M
在大多数宫颈癌中，高危粘膜浸润性人乳头瘤病毒（HPV）（如16型）的DNA被维持以表达两种病毒蛋白E6和E7，这表明对致癌作用至关重要。已知高危HPV E6蛋白抑制p53肿瘤抑制蛋白，但似乎具有额外的分子未知功能。在这项研究中，我们证明这些E6蛋白可以通过它们的C-末端XS/TXV/L（其中X代表任何氨基酸，S/T丝氨酸或苏氨酸，V/L缬氨酸或亮氨酸）基序与果蝇盘状大肿瘤抑制蛋白（hDLG）的人类同源物的第二PDZ结构域结合，这一发现类似于腺瘤性息肉病基因产物与hDLG之间的相互作用。失去与hDLG结合能力的E6突变体不再能够诱导啮齿动物细胞的E6依赖性转化。这些结果表明，E6蛋白与hDLG或其他含PDZ结构域的蛋白之间的相互作用可能是HPV相关癌症发展的潜在机制。
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.