EFFICIENCY OF BINDING THE RETINOBLASTOMA PROTEIN CORRELATES WITH THE TRANSFORMING CAPACITY OF THE E7 ONCOPROTEINS OF THE HUMAN PAPILLOMAVIRUSES
EFFICIENCY OF BINDING THE RETINOBLASTOMA PROTEIN CORRELATES WITH THE TRANSFORMING CAPACITY OF THE E7 ONCOPROTEINS OF THE HUMAN PAPILLOMAVIRUSES
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DOI：
10.1073/pnas.89.10.4442
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发表时间：
1992-05-15
影响因子：
11.1
通讯作者：
MUNGER, K
中科院分区：
文献类型：
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作者：
HECK, DV;YEE, CL;MUNGER, K
与生殖道病变相关的人乳头瘤病毒（hpv）根据其与人类肛门生殖器癌的关联可分为“高风险”或“低风险”。E7蛋白。高风险病毒和低风险病毒在氨基酸组成和结构组织上非常相似，但在转化潜力和许多生化特性上有所不同。构建了一系列由高风险HPV-16和低风险HPV-6 E7蛋白片段组成的嵌合蛋白，以确定E7的氨基末端一半中的哪些结构域负责不同的生物学和生化特性。E7的致癌能力是通过检测幼鼠肾细胞与激活的ras癌基因的转化来确定的，该癌基因与HPV-16 E7蛋白的视网膜母细胞瘤肿瘤抑制蛋白（pRB）结合域分离。对生殖道hpv序列的pRB结合位点的比较显示，高风险和低风险病毒之间存在一致的氨基酸差异（天冬氨酸/甘氨酸）。在HPV-6和HPV-16 E7蛋白的这一位置产生了单氨基酸替代突变，这一单氨基酸残基被证明是区分高危和低危HPV E7蛋白的pRB结合亲和力和转化能力差异的主要决定因素。
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.