The E7 oncoprotein associates with Mi2 and histone deacetylase activity to promote cell growth
The E7 oncoprotein associates with Mi2 and histone deacetylase activity to promote cell growth
复制标题
DOI：
10.1093/emboj/18.9.2449
复制
发表时间：
1999-05-04
期刊：
影响因子：
11.4
通讯作者：
Kouzarides, T
中科院分区：
文献类型：
--
作者：
Brehm, A;Nielsen, SJ;Kouzarides, T
E7是人乳头瘤病毒16型（HPV 16）的主要转化蛋白，其与宫颈癌的形成有关。E7的转化活性归因于其与视网膜母细胞瘤（Rb）肿瘤抑制因子的相互作用。然而，Rb结合对于E7的转化是不充分的。锌指结构域内的突变（其对于Rb结合是不充分的）也消除E7转化功能。在这里，我们表明，HPV 16 E7与组蛋白脱乙酰酶在体外和体内，通过其锌指结构域。使用遗传筛选，我们确定Mi2 β，最近确定的CD3D组蛋白脱乙酰酶复合物的一个组成部分，作为一种蛋白质，直接结合到E7锌指。不能结合Mi2 β和组蛋白脱乙酰酶但仍能结合Rb的锌指点突变体未能克服骨肉瘤细胞中的细胞周期停滞。我们的结果表明，与组蛋白脱乙酰酶复合物的结合是人乳头瘤病毒E7蛋白促生长活性的重要参数。这提供了病毒癌蛋白通过靶向去乙酰化途径控制细胞增殖的第一个迹象。
E7 is the main transforming protein of human papilloma virus type 16 (HPV16) which is implicated in the formation of cervical cancer. The transforming activity of E7 has been attributed to its interaction with the retinoblastoma (Rb) tumour suppressor. However, Rb binding is not sufficient for transformation by E7, Mutations within a zinc finger domain, which is dispensable for Rb binding, also abolish E7 transformation functions. Here we show that HPV16 E7 associates with histone deacetylase in vitro and in vivo, via its zinc finger domain. Using a genetic screen, we identify Mi2 beta, a component of the recently identified NURD histone deacetylase complex, as a protein that binds directly to the E7 zinc finger. A zinc finger point mutant which is unable to bind Mi2 beta and histone deacetylase but is still able to bind Rb fails to overcome cell cycle arrest in osteosarcoma cells. Our results suggest that the binding to a histone deacetylase complex is an important parameter for the growth-promoting activity of the human papilloma virus E7 protein. This provides the first indication that viral oncoproteins control cell proliferation by targeting deacetylation pathways.