Institute of Biomedical Sciences, College of Life Science, East China Normal University, Shanghai 200241, PR China.
Biochem J. 2011 Mar 1;434(2):275-85. doi: 10.1042/BJ20101163.
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.
肿瘤抑制因子 ARF（交替阅读框）是最重要的致癌应激传感器之一。ARF 通过 p53 依赖和非依赖机制提供“致癌检查点”功能。在本研究中，我们证明了 p14(ARF) 和腺病毒致癌蛋白 E1A 之间存在一种新的 p53 非依赖性相互作用。p14(ARF) 抑制 E1A 的转录功能，并促进 E1A 的泛素化依赖性降解。p14(ARF) 的过表达将 E1A 重新定位到核仁中，并独立于 p53 抑制 E1A 诱导的细胞 DNA 复制。内源性 p14(ARF) 的敲低增加了 E1A 的反式激活。此外，E1A 可以竞争性抑制 ARF-Mdm2（鼠双微体 2）复合物的形成。这些结果确定了 p14(ARF) 的一个新结合伙伴，并揭示了 p14(ARF) 和 E1A 之间的相互抑制相互作用。我们推测，ARF-E1A 相互作用可能代表限制病毒复制的另一种宿主防御机制。或者，这种相互作用可能允许腺病毒感知宿主细胞中 p53 的功能状态，并精细调整其自身的复制活性，以防止触发有害的宿主反应。
