腺病毒E4orf4蛋白诱导的肿瘤特异性细胞死亡及其在癌症治疗中的应用

Tumor-specific Cell Deaths Induced by the Adenovirus E4orf4 Protein and Its Application in Cancer Therapy

腺病毒E4orf4蛋白由腺病毒早期第4转录区第4开放读码框编码,为一种多功能调节蛋白质,其活性包括下调早期病毒基因表达和下调影响病毒复制的细胞基因表达,调控病毒基因的选择性转录后剪切以影响病毒感染进程等。当E4orf4脱离病毒环境单独表达时,可诱导不依赖p53和胱天蛋白酶途径的癌细胞特异性细胞死亡,而不影响原代细胞的正常生长。这表明E4orf4对癌细胞有特异性的杀伤作用。本文主要介绍了:(1)E4orf4主要蛋白质伴侣(蛋白磷酸酶2A和Src家族激酶)对E4orf4细胞杀伤作用的贡献;(2)E4orf4诱导的细胞死亡独特模式的基本机制及其特点;(3)近年来利用E4orf4治疗癌症的研究。

The adenovirus E4orf4 protein is encoded by the adenovirus early region 4 open reading frame 4. It is a multifunctional viral regulator that contributes to the down-regulation of viral and cellular genes expression, which affects viral replication and the alternative splicing of viral mRNAs. When expressed alone, E4orf4 induces nonclassical cancer-specific cell deaths that are caspase-independent and p53- independent in many transformed cells, indicating that E4orf4 may be exploited for cancer therapy. In this review, we overview the following points： （1） the contribution of E4orf4 interaction partners （protein phosphatase 2 A and the Src family kinase） to E4orf4-induced cell deaths in the nucleus and cytoplasm; （2） the unique mechanisms of E4orf4-induced cell deaths and its cancer specificity; （3） recent progress of E4orf4 in cancer therapy.