Kumar Ajay, Zhao Yongtong, Meng Gaoyuan, Zeng Musheng, Srinivasan Seetha, Delmolino Laurie M, Gao Qingshen, Dimri Goberdhan, Weber Georg F, Wazer David E, Band Hamid, Band Vimla
Division of Radiation and Cancer Biology, Department of Radiation Oncology, New England Medical Center, Boston, Massachusetts 02111, USA.
Mol Cell Biol. 2002 Aug;22(16):5801-12. doi: 10.1128/MCB.22.16.5801-5812.2002.
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(1) 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.
高危型人乳头瘤病毒（HPV）与宫颈癌及其他生殖器肿瘤相关。HPV致癌蛋白E6对于致癌转化至关重要。我们在此鉴定出酵母转录共激活因子yADA3的人类同源物hADA3，它是一种新型的E6相互作用蛋白，也是E6诱导降解的靶点。hADA3选择性地与高危型HPV E6蛋白结合，且仅与具有永生化能力的E6突变体结合。hADA3通过稳定p53蛋白发挥p53介导的反式激活共激活因子的作用。值得注意的是，三种不诱导直接p53降解但与hADA3相互作用的永生化E6突变体，在DNA损伤后诱导p53介导的反式激活和G(1)期细胞周期停滞被废除，这与野生型E6相当。这些发现揭示了一种HPV E6诱导p53功能丧失的新策略，该策略独立于直接的p53降解。鉴于进化保守的hADA3可能在多种共激活因子复合物中发挥作用，其功能失活可能使E6在HPV致癌过程中扰乱众多细胞通路。
