C-terminal-binding protein interacting protein binds directly to adenovirus early region 1A through its N-terminal region and conserved region 3
C-terminal-binding protein interacting protein binds directly to adenovirus early region 1A through its N-terminal region and conserved region 3
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DOI：
10.1038/sj.onc.1210551
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发表时间：
2007-11-22
期刊：
影响因子：
8
通讯作者：
Grand, R. J. A.
中科院分区：
文献类型：
--
作者：
Bruton, R. K.;Rasti, M.;Grand, R. J. A.
C-末端结合蛋白相互作用蛋白（CtIP）作为C-末端结合蛋白（CtBP）的结合伴侣而被首次分离。它被认为有助于视网膜母细胞瘤（Rb）蛋白家族的转录抑制和细胞周期调节特性，并在细胞对DNA损伤的反应中发挥作用。在这里，我们已经表明，CtIP是一个新的目标腺病毒癌蛋白早期区域1A（AdE 1A）。AdE 1A在Ad 5E 1转化的细胞和Ad 5感染的细胞中与CtIP结合，并在谷胱甘肽-S-转移酶下拉测定中直接结合。已在Ad 5E 1A上定位了两个结合位点-N-末端α-螺旋区（残基1 - 30）和保守区3（CR 3）-转录激活结构域。CtIP可以独立地结合AdE 1A和CtBP，提高了在Ad转化和感染的细胞中存在三元复合物的可能性。值得注意的是，用小干扰RNA减少CtIP表达导致Gal 4 DNA结合结构域-CR 3构建体反式激活Gal 4响应性荧光素酶报告基因的能力降低，并且这种作用通过减少CtBP表达而逆转。因此，在该模型中，CtIP在与CtBP解离时通过AdE 1A的作用充当AdE 1A的转录共激活因子。这些数据与观察结果一致，即在病毒感染期间AdE 1A诱导CtIP表达，并且RNA干扰减少CtIP表达可以延缓病毒复制。此外，AdE 1A通过与CtIP的相互作用在病毒感染期间引起CtIP/Rb复合物的破坏，可能有助于转录去抑制。
C-terminal-binding protein interacting protein (CtIP) was first isolated as a binding partner of C-terminal-binding protein (CtBP). It is considered to contribute to the transcriptional repression and cell cycle regulatory properties of the retinoblastoma (Rb) family of proteins and to have a role in the cellular response to DNA damage. Here, we have shown that CtIP is a novel target for the adenovirus oncoprotein early region 1A (AdE1A). AdE1A associates with CtIP in both Ad5E1-transformed cells and Ad5-infected cells and binds directly in glutathione-S-transferase pull-down assays. Two binding sites have been mapped on Ad5E1A - the N-terminal alpha-helical region ( residues 1 - 30) and conserved region 3(CR3) - the transcriptional activation domain. CtIP can bind AdE1A and CtBP independently, raising the possibility that ternary complexes exist in Ad-transformed and - infected cells. Significantly, reduction of CtIP expression with small interfering RNAs results in reduction of the ability of a Gal4 DNA-binding domain-CR3 construct to transactivate a Gal 4-responsive luciferase reporter and this effect is reversed by reduction of CtBP expression. Therefore, in this model, CtIP acts as a transcriptional co-activator of AdE1A when dissociated from CtBP, through the action of AdE1A. These data are consistent with observations that CtIP expression is induced by AdE1A during viral infection and that reduction of CtIP expression with RNA interference can retard virus replication. In addition, AdE1A causes disruption of the CtIP/Rb complex during viral infection by its interaction with CtIP, possibly contributing to transcriptional derepression.