Backendorf Claude, Visser Astrid E, de Boer A G, Zimmerman Rhyenne, Visser Mijke, Voskamp Patrick, Zhang Ying-Hui, Noteborn Mathieu
Molecular Genetics, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
Annu Rev Pharmacol Toxicol. 2008;48:143-69. doi: 10.1146/annurev.pharmtox.48.121806.154910.
The avian virus-derived protein apoptin induces p53-independent apoptosis in a tumor-specific way. Apoptin acts as a multimeric complex and forms superstructures upon binding to DNA. In tumor cells, apoptin is phosphorylated and mainly nuclear, whereas in normal cells it is unphosphorylated, cytoplasmic, and becomes readily neutralized. Interestingly, apoptin phosphorylation, nuclear translocation, and apoptosis can transiently be induced in normal cells by cotransfecting SV40 large T oncogene, indicating that apoptin recognizes early stages of oncogenic transformation. In cancer cells, apoptin appears to recognize survival signals, which it is able to redirect into cell death impulses. Apoptin targets include DEDAF, Nur77, Nmi, Hippi, and the potential drug target APC1. Apoptin-transgenic mice and animal tumor models have revealed apoptin as a safe and efficient antitumor agent, resulting in significant tumor regression. Future antitumor therapies could use apoptin either as a therapeutic bullet or as an early sensor of druggable tumor-specific processes.
禽源病毒蛋白凋亡素以肿瘤特异性方式诱导不依赖p53的细胞凋亡。凋亡素以多聚体复合物形式发挥作用，与DNA结合后形成超结构。在肿瘤细胞中，凋亡素被磷酸化且主要位于细胞核内，而在正常细胞中它未被磷酸化，位于细胞质中且容易被中和。有趣的是，通过共转染SV40大T癌基因可在正常细胞中短暂诱导凋亡素磷酸化、核转位及细胞凋亡，这表明凋亡素能识别致癌转化的早期阶段。在癌细胞中，凋亡素似乎能识别存活信号，并将其重定向为细胞死亡信号。凋亡素的作用靶点包括DEDAF、Nur77、Nmi、Hippi以及潜在的药物靶点APC1。凋亡素转基因小鼠和动物肿瘤模型已表明凋亡素是一种安全有效的抗肿瘤药物，可导致肿瘤显著消退。未来的抗肿瘤治疗可将凋亡素用作治疗手段或可药物治疗的肿瘤特异性过程的早期传感器。
