Cellular steady-state levels of "high risk" but not "low risk" human papillomavirus (HPV) E6 proteins are increased by inhibition of proteasome-dependent degradation independent of their p53-and E6AP-binding capabilities
Cellular steady-state levels of "high risk" but not "low risk" human papillomavirus (HPV) E6 proteins are increased by inhibition of proteasome-dependent degradation independent of their p53-and E6AP-binding capabilities
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DOI：
10.1006/viro.2002.1502
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发表时间：
2002-07-20
期刊：
影响因子：
3.7
通讯作者：
Stöppler, H
中科院分区：
文献类型：
--
作者：
Kehmeier, E;Rühl, H;Stöppler, H
感染粘膜上皮的人乳头瘤病毒（HPV）组可细分为“低”和“高风险”HPV类型。这两种类型都会诱发良性瘤形成（湿疣），但只有“高危”HPV类型的感染与发生肛门生殖器肿瘤的风险增加有因果关系。高危HPV的致癌潜力至少部分在于病毒E6蛋白。E6蛋白靶向细胞p53蛋白进行蛋白酶体依赖性降解，这与这些病毒的永生化和转化功能有关。最近，已经描述了E6依赖性蛋白酶体介导的其他细胞蛋白（E6 TP 1、c-myc、巴克、hMCM 7、人scribble、E6 AP、MAGI-1）的不稳定化，但迄今为止尚未分析控制病毒E6蛋白稳定性本身的细胞机制。在这项研究中，我们瞬时表达E6基因的高危型HPV 16型，低危型HPV 6a和11型，和皮肤上皮感染的HPV 5型和8型从真核表达载体，并比较细胞稳态水平的表达E6蛋白。我们证明，高风险HPV 16 E6蛋白具有最低的稳态水平相比，低风险HPV E6型蛋白和皮肤上皮感染HPV E6型蛋白。细胞蛋白酶体依赖性蛋白降解的抑制导致高风险但不是低风险E6蛋白的稳态水平增加。在p53空表达细胞系和p53野生型表达细胞系中分析功能缺陷的HPV 16 E6蛋白揭示了该蛋白的细胞稳态水平既不受其p53结合能力也不受其E6 AP结合能力的影响。(C)2002 Elsevier Science（美国）。
The group of mucosal epithelia-infecting human papillomaviruses (HPV) can be subdivided in "low" and "high risk" HPV types. Both types induce benign neoplasia (condyloma), but only the infection with a "high risk" HPV type is causally associated with an increased risk of developing anogenital tumors. The oncogenic potential of high risk HPVs resides at least partially in the viral E6 protein. The E6 protein targets the cellular p53 protein for proteasome-dependent degradation, which is associated with the immortalizing and transforming functions of these viruses. Recently the E6-dependent proteasome-mediated destabilization of additional cellular proteins (E6TP1, c-myc, Bak, hMCM7, human scribble, E6AP, MAGI-1) has been described, but the cellular mechanisms controlling the viral E6 protein stability itself have been so far not analyzed. In this study, we transiently expressed the E6 genes of the high risk HPV type 16, the low risk HPV types 6a and 11, and the cutaneous epithelia-infecting HPV types 5 and 8 from a eucaryotic expression vector and compared the cellular steady-state levels of the expressed E6 proteins. We demonstrated that the high risk HPV 16 E6 protein possesses the lowest steady-state level in comparison to the low risk HPV type E6 proteins and the cutaneous epithelia-infecting HPV type E6 proteins. Inhibition of cellular proteasome-dependent protein degradation led to an increase in steady-state levels of high risk but not of low risk E6 proteins. Analysis of functionally deficient HPV 16 E6 proteins in p53 null- and p53 wild-type-expressing cell lines revealed that the cellular steady-state level of this protein is influenced neither by its p53- nor its E6AP-binding abilities. (C) 2002 Elsevier Science (USA).