THE ABILITY OF HUMAN PAPILLOMAVIRUS E6 PROTEINS TO TARGET P53 FOR DEGRADATION IN-VIVO CORRELATES WITH THEIR ABILITY TO ABROGATE ACTINOMYCIN D-INDUCED GROWTH ARREST
THE ABILITY OF HUMAN PAPILLOMAVIRUS E6 PROTEINS TO TARGET P53 FOR DEGRADATION IN-VIVO CORRELATES WITH THEIR ABILITY TO ABROGATE ACTINOMYCIN D-INDUCED GROWTH ARREST
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DOI：
10.1128/jvi.68.9.5698-5705.1994
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发表时间：
1994-09-01
影响因子：
5.4
通讯作者：
GALLOWAY, DA
中科院分区：
文献类型：
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作者：
FOSTER, SA;DEMERS, GW;GALLOWAY, DA
功能性 p53 蛋白与 DNA 损伤后细胞在 G 期停滞的能力相关。癌症相关人乳头瘤病毒 16 型 (HPV-16) 的 E6 蛋白与 p53 结合，并通过泛素途径靶向其降解。为了确定 E6 与 p53 相互作用的能力是否会导致细胞周期控制的破坏，我们测试了突变 E6 蛋白的体外 p53 结合和 p53 降解靶向、体内降低细胞内 p53 水平的能力，以及消除放线菌素 D 诱导的人角质形成细胞生长停滞的能力。分散在整个氨基末端（锌指或中心区域，但不是羧基末端）的突变严重降低了 E6 与 p53 相互作用的能力。 HPV-16 E6 或突变 E6 蛋白的表达结合并靶向 p53 进行体外降解，急剧降低了人角质形成细胞中放线菌素 D 诱导的细胞内 p53 水平。观察到 E6 蛋白降低细胞内 p53 水平的能力与其阻断放线菌素 D 诱导的细胞生长停滞的能力之间存在完美的相关性。这些结果表明，与 p53 的相互作用对于 HPV E6 蛋白规避生长停滞的能力非常重要。
Functional p53 protein is associated with the ability of cells to arrest in G, after DNA damage. The E6 protein of cancer-associated human papillomavirus type 16 (HPV-16) binds to p53 and targets its degradation through the ubiquitin pathway. To determine whether the ability of E6 to interact with p53 leads to a disruption of cell cycle control, mutated E6 proteins were tested for p53 binding and p53 degradation targeting in vitro, the ability to reduce intracellular p53 levels in vivo, and the ability to abrogate actinomycin D-induced growth arrest in human keratinocytes. Mutations scattered throughout the amino terminus, either zinc finger or the central region but not the carboxy terminus, severely reduced the ability of E6 to interact with p53. Expression of HPV-16 E6 or mutated E6 proteins that bound and targeted p53 for degradation in vitro sharply reduced the level of intracellular p53 induced by actinomycin D in human keratinocytes. A perfect correlation between the ability of E6 proteins to reduce the level of intracellular p53 and their ability to block actinomycin D-induced cellular grow th arrest was observed. These results suggest that interaction with p53 is important for the ability of HPV E6 proteins to circumvent growth arrest.