p14ARF inhibits the functions of adenovirus E1A oncoprotein
p14ARF inhibits the functions of adenovirus E1A oncoprotein
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DOI：
10.1042/bj20101163
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发表时间：
2011-03-01
影响因子：
4.1
通讯作者：
Wang, Chuangui
中科院分区：
文献类型：
--
作者：
Shen, Jia;Zhang, Shengping;Wang, Chuangui
肿瘤抑制因子ARF（alternative阅读frame）是最重要的致癌应激感受器之一。ARF通过p53依赖性和p53非依赖性机制提供“致癌检查点”功能。在本研究中，我们证明了一种新的p53-独立的p14（ARF）和腺病毒癌蛋白E1 A之间的相互作用。p14（ARF）抑制E1 A转录功能并促进E1 A的泛素化依赖性降解。p14（ARF）过表达将E1 A重新定位到核仁中，并抑制E1 A诱导的细胞DNA复制，而不依赖于p53。内源性p14（ARF）的敲低增加E1 A反式激活。此外，E1 A可竞争性抑制ARF-Mdm 2（鼠双微体2）复合物的形成。这些结果确定了一种新的p14（ARF）的结合伴侣，并揭示了p14（ARF）和E1 A之间的相互抑制作用。我们推测ARF-E1 A相互作用可能代表了限制病毒复制的额外宿主防御机制。或者，这种相互作用可以允许腺病毒感知宿主细胞中p53的功能状态，并微调其自身的复制活性以防止触发有害的宿主反应。
The tumour suppressor ARF (alternative reading frame) is one of the most important oncogenic stress sensors. ARF provides an 'oncogenic checkpoint' function through both p53-dependent and p53-independent mechanisms. In the present study, we demonstrate a novel p53-independent interaction between p14(ARF) and the adenovirus oncoprotein E1A. p14(ARF) inhibits E1A transcriptional function and promotes ubiquitination-dependent degradation of E1A. p14(ARF) overexpression relocalizes E1A into the nucleolus and inhibits E1A-induced cellular DNA replication independent of p53. Knockdown of endogenous p14(ARF) increases E1A transactivation. In addition, E1A can competitively inhibit ARF-Mdm2 (murine double minute 2) complex formation. These results identify a novel binding partner of p14(ARF) and reveal a mutually inhibitory interaction between p14(ARF) and E1A. We speculate that the ARF-E1A interaction may represent an additional host defence mechanism to limit viral replication. Alternatively, the interaction may allow adenovirus to sense the functional state of p53 in host cells, and fine-tune its own replication activity to prevent the triggering of a detrimental host response.