Bell L A, O'Prey J, Ryan K M
Tumour Cell Death Laboratory, Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Garscube Estate, Glasgow, UK.
Oncogene. 2006 Sep 14;25(41):5656-63. doi: 10.1038/sj.onc.1209580. Epub 2006 May 1.
The ability to induce cell cycle progression while evading cell death is a defining characteristic of cancer. Deregulation of E2F is a common event in most human cancers. Paradoxically, this can lead to both cell cycle progression and apoptosis. Although the way in which E2F causes cell cycle progression is well characterized, the pathways by which E2F induces cell death are less well defined. Many of the known mechanisms through which E2F induces apoptosis occur through regulation of E2F target genes. However, mutants of E2F-1 that lack the transactivation domain are still able to induce cell death. To further investigate this activity, we refined a transactivation independent mutant to identify a minimal apoptotic domain. This revealed that only 75 amino acids from within the DNA-binding domain of E2F-1 is sufficient for cell death and that this activity is also present in the DNA-binding domains of E2F-2 and E2F-3. However, analysis of this domain from E2F-1 revealed it does not bind DNA and is consequently unable to transactivate, repress or de-repress E2F target genes. This provocative observation therefore defines a potential new mechanism of death from E2F and opens up new opportunities for inducing cell death in tumours for therapeutic gain.
能够在逃避细胞死亡的同时诱导细胞周期进程是癌症的一个决定性特征。E2F失调在大多数人类癌症中是常见事件。矛盾的是，这既能导致细胞周期进程，也能引发细胞凋亡。尽管E2F导致细胞周期进程的方式已得到充分表征，但E2F诱导细胞死亡的途径却不太明确。许多已知的E2F诱导凋亡的机制是通过调控E2F靶基因发生的。然而，缺乏反式激活结构域的E2F-1突变体仍能诱导细胞死亡。为了进一步研究这种活性，我们对一个不依赖反式激活的突变体进行了优化，以确定一个最小的凋亡结构域。这表明，E2F-1的DNA结合结构域中只有75个氨基酸就足以导致细胞死亡，并且这种活性在E2F-2和E2F-3的DNA结合结构域中也存在。然而，对E2F-1的这个结构域的分析表明它不结合DNA，因此无法反式激活、抑制或去抑制E2F靶基因。因此，这一引人深思的观察结果定义了一种潜在的E2F诱导死亡的新机制，并为在肿瘤中诱导细胞死亡以实现治疗获益开辟了新的机会。
