Human papillomavirus type 16 E7 oncoprotein associates with the cullin 2 ubiquitin ligase complex, which contributes to degradation of the retinoblastoma tumor suppressor
Human papillomavirus type 16 E7 oncoprotein associates with the cullin 2 ubiquitin ligase complex, which contributes to degradation of the retinoblastoma tumor suppressor
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DOI：
10.1128/jvi.00881-07
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发表时间：
2007-09-01
影响因子：
5.4
通讯作者：
Munger, Karl
中科院分区：
文献类型：
--
作者：
Huh, KyungWon;Zhou, Xiaobo;Munger, Karl
人乳头瘤病毒16型(HPV16)和其他高危HPV在病因学上与宫颈癌的发展有关，并导致其他一些肛门生殖道肿瘤以及口腔癌。高危HPVE6和E7癌蛋白在宫颈癌细胞中持续表达，是诱导和维持转化表型所必需的。HPV16ETS致癌活性的一个重要方面是通过泛素/蛋白酶体依赖的机制使视网膜母细胞瘤肿瘤抑制因子(PRB)失稳，尽管确切的分子机制尚不清楚。在这里，我们报道了HPV16 E7与一个酶活性的cullin 2泛素连接酶复合体有关，HPV16 E7/pRb复合体包含cullin 2。RNA干扰去除cullin 2导致表达HPV16 E7的细胞中pRb的稳态水平和稳定性增加，而HPV16 E7和cullin 2复合体的异位表达导致体内pRb泛素化。因此，我们认为HPV16E7相关的cullin 2泛素连接酶复合体在表达HPV16E7的细胞中有助于pRb肿瘤抑制因子的异常降解。
Human papillomavirus type 16 (HPV16) and other high-risk HPVs are etiologically linked to the development of cervical carcinomas and contribute to a number of other tumors of the anogenital tract, as well as oral cancers. The high-risk HPV E6 and E7 oncoproteins are consistently expressed in cervical cancer cells and are necessary for the induction and maintenance of the transformed phenotype. An important aspect of HPV16 ETs oncogenic activities is destabilization of the retinoblastoma tumor suppressor (pRB) through a ubiquitin/proteasome-dependent mechanism, although the exact molecular mechanism is unknown. Here, we report that HPV16 E7 is associated with an enzymatically active cullin 2 ubiquitin ligase complex and that the HPV16 E7/pRB complex contains cullin 2. Depletion of cullin 2 by RNA interference causes increased steady-state levels and stability of pRB in HPV16 E7-expressing cells, and ectopic expression of HPV16 E7 and the cullin 2 complex leads to pRB ubiquitination in vivo. Hence, we propose that the HPV16 E7-associated cullin 2 ubiquitin ligase complex contributes to aberrant degradation of the pRB tumor suppressor in HPV16 E7-expressing cells.