Human papillomavirus oncoprotein E6 inactivates the transcriptional coactivator human ADA3
Human papillomavirus oncoprotein E6 inactivates the transcriptional coactivator human ADA3
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DOI：
10.1128/mcb.22.16.5801-5812.2002
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发表时间：
2002-08-01
影响因子：
5.3
通讯作者：
Band, V
中科院分区：
文献类型：
--
作者：
Kumar, A;Zhao, YT;Band, V
高危型人乳头瘤病毒（HPV）与宫颈癌和其他生殖器肿瘤有关。HPV癌蛋白E6是致癌转化所必需的。我们在这里确定hADA 3，人类同源的酵母转录共激活因子yADA 3，作为一种新的E6相互作用的蛋白质和E6诱导的降解的目标。hADA 3选择性地结合高危HPV E6蛋白，并且仅结合永生化能力的E6突变体。hADA 3通过稳定p53蛋白而作为p53介导的反式激活的共激活剂起作用。值得注意的是，三个不诱导直接p53降解，但与hADA 3相互作用的永生化E6突变体诱导废除p53介导的反式激活和G，DNA损伤后的细胞周期停滞，与野生型E6。这些发现揭示了HPV E6诱导的p53功能丧失的新策略，其独立于直接p53降解。考虑到进化上保守的hADA 3在多种共激活因子复合物中的可能作用，其功能的失活可能使E6在HPV肿瘤发生期间扰乱许多细胞途径。
High-risk human papillomaviruses (HPVs) are associated with carcinomas of the cervix and other genital tumors. The HPV oncoprotein E6 is essential for oncogenic transformation. We identify here hADA3, human homologue of the yeast transcriptional coactivator yADA3, as a novel E6-interacting protein and a target of E6-induced degradation. hADA3 binds selectively to the high-risk HPV E6 proteins and only to immortalization-competent E6 mutants. hADA3 functions as a coactivator for p53-mediated transactivation by stabilizing p53 protein. Notably, three immortalizing E6 mutants that do not induce direct p53 degradation but do interact with hADA3 induced the abrogation of p53-mediated transactivation and G, cell cycle arrest after DNA damage, comparable to wild-type E6. These findings reveal a novel strategy of HPV E6-induced loss of p53 function that is independent of direct p53 degradation. Given the likely role of the evolutionarily conserved hADA3 in multiple coactivator complexes, inactivation of its function may allow E6 to perturb numerous cellular pathways during HPV oncogenesis.