Tumour Suppression Laboratory, The Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Oncogene. 2013 Jul 25;32(30):3510-9. doi: 10.1038/onc.2012.365. Epub 2012 Sep 17.
The E6AP E3 ubiquitin ligase has been linked to the regulation of cell growth and to the cellular stress response. However, the specific stress conditions that are controlled by E6AP have not been defined. An important stress condition that controls cell growth is oxidative stress, where the levels of intracellular reactive oxygen species (ROS) regulate the appropriate cellular response. Here, we describe a novel role for E6AP in the control of oxidative stress response. Cells lacking E6AP expression have reduced capacity to accumulate ROS, and oxidative DNA damage, in response to 20% cell culture oxygen levels, treatment with hydrogen peroxide and expression of oncogenic RAS. This effect of E6AP is associated with the regulation of the anti-oxidant enzyme, Prx1, a previously identified target of E6AP, and can be corrected by downregulation of Prx1 or by reconstitution of E6AP expression. Consequently, cells with compromised E6AP have impaired senescent and apoptotic response to sub-lethal and lethal doses of oxidative stress, respectively. In a xenograft model, downregulation of E6AP renders transplanted tumours refractory to growth-suppressive effects of hydrogen peroxide. Our results provide the first demonstration that E6AP is an important regulator of ROS-mediated cellular senescence and cell death.
E6AP E3 泛素连接酶与细胞生长的调节和细胞应激反应有关。然而，E6AP 控制的特定应激条件尚未确定。控制细胞生长的一个重要应激条件是氧化应激，细胞内活性氧（ROS）的水平调节适当的细胞反应。在这里，我们描述了 E6AP 在控制氧化应激反应中的一个新作用。缺乏 E6AP 表达的细胞在 20%细胞培养氧水平、过氧化氢处理和致癌 RAS 表达时，ROS 的积累和氧化 DNA 损伤的能力降低。E6AP 的这种作用与抗氧化酶 Prx1 的调节有关，Prx1 是 E6AP 的先前确定的靶标，下调 Prx1 或重建 E6AP 的表达可以纠正这种作用。因此，E6AP 功能受损的细胞对亚致死和致死剂量的氧化应激的衰老和凋亡反应受损。在异种移植模型中，下调 E6AP 使移植瘤对过氧化氢的生长抑制作用产生抗性。我们的结果首次证明 E6AP 是 ROS 介导的细胞衰老和细胞死亡的重要调节因子。
