DNA-binding independent cell death from a minimal proapoptotic region of E2F-1
DNA-binding independent cell death from a minimal proapoptotic region of E2F-1
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DOI：
10.1038/sj.onc.1209580
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发表时间：
2006-09-14
期刊：
影响因子：
8
通讯作者：
Ryan, K. M.
中科院分区：
文献类型：
--
作者：
Bell, L. A.;O'Prey, J.;Ryan, K. M.
诱导细胞周期进程同时避免细胞死亡的能力是一种能力。癌症的宁特征。 E2F 失调是大多数人类癌症中的常见事件。矛盾的是，这可能导致细胞周期进展和细胞凋亡。尽管 E2F 引起细胞周期进展的方式已得到很好的表征，但 E2F 诱导细胞死亡的途径尚不清楚。 E2F 诱导细胞凋亡的许多已知机制是通过调节 E2F 靶基因发生的。然而，缺乏反式激活结构域的 E2F-1 突变体仍然能够诱导细胞死亡。为了进一步研究这种活性，我们精炼了一种独立于反式激活的突变体，以鉴定最小的凋亡结构域。这表明，E2F-1 DNA 结合结构域内仅 75 个氨基酸足以导致细胞死亡，并且这种活性也存在于 E2F-2 和 E2F-3 的 DNA 结合结构域中。然而，对 E2F-1 的该结构域的分析表明，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，这一令人兴奋的观察结果定义了 E2F 潜在的新死亡机制，并为诱导肿瘤细胞死亡以获得治疗效果开辟了新的机会。
The ability to induce cell cycle progression while evading cell death is a de. ning 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 derepress 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.