Degradation of HPV20E6 by p53:: ΔNp63α and mutant p53R248W protect the wild type p53 mediated caspase-degradation
Degradation of HPV20E6 by p53:: ΔNp63α and mutant p53R248W protect the wild type p53 mediated caspase-degradation
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DOI：
10.1002/ijc.23506
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发表时间：
2008-07-01
影响因子：
6.4
通讯作者：
de Villiers, Ethel-Michele
中科院分区：
文献类型：
--
作者：
Fei, Jian-Wei;de Villiers, Ethel-Michele
人乳头瘤病毒（HPV）的E6和E7蛋白在恶性肿瘤的发病机制中发挥着至关重要的作用。高危粘膜乳头瘤病毒的 E6 蛋白通过与泛素连接酶 E6AP 形成复合物，靶向多种蛋白进行蛋白体降解。这些蛋白质包括 p53、桩蛋白和 PDZ 结构域蛋白，例如 p53、paxillin 和 PDZ 结构域蛋白。挖掘和玛格克。尽管已知广泛的紫外线照射和 p53 突变（热点突变）与非黑色素瘤皮肤癌有关，但皮肤 HPV 类型的 E6 蛋白与细胞蛋白相互作用诱导良性或恶性皮肤病变的机制尚未阐明。我们证明了 HPV20E6 可能参与感染细胞的两种机制。一种途径是 wtp53 通过 caspase-3 介导的 HPV20E6 降解。突变的 p53R248W 和 Delta Np63 α，以及参与蛋白酶体依赖性降解的其他未知蛋白质，在这些条件下对 HPV20E6 具有保护作用。这揭示了与 E6-E6AP 介导的粘膜 HPV 类型 p53 降解的众所周知机制相反的显着调节。在第二次相互作用中，异位表达的 HPV20E6 诱导 proaspase-3 裂解为活性 caspase-3。此外，我们还证明了 HPV20E6 与中间丝波形蛋白的体内结合。 (C) 2008 Wiley-Liss, Inc.
The E6 and E7 proteins of human papillomaviruses (HPV) play a crucial role in the pathogenesis of malignant tumors. E6 protein of high-risk mucosal papillomaviruses targets a number of proteins for proteosomal degradation through complex formation with ubiquitin ligase E6AP. These proteins include, amongst others, p53, paxillin and PDZ-domain proteins e.g. Dig and MAGUK. The mechanism by which the E6 protein of cutaneous HPV types interacts with cellular proteins to induce either benign or malignant cutaneous lesions, has not been elucidated, although extensive ultraviolet exposure and mutated p53 (hot-spot mutations) are known to be associated with non-melanoma skin cancer. We demonstrate two mechanisms in which HPV20E6 may be involved in the infected cell. One pathway is the wtp53 mediated degradation of HPV20E6 through caspase-3. Mutated p53R248W and Delta Np63 alpha, as well as other unknown proteins involved in proteosome-dependent degradation, convey a protective effect on HPV20E6 under these conditions. This unveils a remarkable opposite regulation to the well-known mechanism of E6-E6AP mediated degradation of p53 for mucosal HPV types. In a second interaction, ectopically expressed HPV20E6 induces cleavage of procaspase-3 to active caspase-3. We demonstrate, in addition, in vivo binding of HPV20E6 to the intermediate filament vimentin. (C) 2008 Wiley-Liss, Inc.