Williams Drew, Norman Grant, Khoury Chamel, Metcalfe Naomi, Briard Jennie, Laporte Aimee, Sheibani Sara, Portt Liam, Mandato Craig A, Greenwood Michael T
Department of Anatomy and Cell Biology, McGill University. Montreal, Quebec, Canada.
Biochim Biophys Acta. 2011 Feb;1813(2):315-21. doi: 10.1016/j.bbamcr.2010.11.021. Epub 2010 Dec 8.
The identification of novel anti-apoptotic sequences has lead to new insights into the mechanisms involved in regulating different forms of programmed cell death. For example, the anti-apoptotic function of free radical scavenging proteins supports the pro-apoptotic function of Reactive Oxygen Species (ROS). Using yeast as a model of eukaryotic mitochondrial apoptosis, we show that a cDNA corresponding to the mitochondrial variant of the human DUT gene (DUT-M) encoding the deoxyuridine triphosphatase (dUTPase) enzyme can prevent apoptosis in yeast in response to internal (Bax expression) and to exogenous (H(2)O(2) and cadmium) stresses. Of interest, cell death was not prevented under culture conditions modeling chronological aging, suggesting that DUT-M only protects dividing cells. The anti-apoptotic function of DUT-M was confirmed by demonstrating that an increase in dUTPase protein levels is sufficient to confer increased resistance to H(2)O(2) in cultured C2C12 mouse skeletal myoblasts. Given that the function of dUTPase is to decrease the levels of dUTP, our results strongly support an emerging role for dUTP as a pro-apoptotic second messenger in the same vein as ROS and ceramide.
新型抗凋亡序列的鉴定为调控不同形式程序性细胞死亡的机制带来了新的见解。例如，自由基清除蛋白的抗凋亡功能支持了活性氧（ROS）的促凋亡功能。以酵母作为真核细胞线粒体凋亡的模型，我们发现，一个与人类DUT基因的线粒体变体（DUT-M）相对应的cDNA，该基因编码脱氧尿苷三磷酸酶（dUTPase），能够在酵母中响应内部（Bax表达）和外部（H₂O₂和镉）应激时防止细胞凋亡。有趣的是，在模拟时序老化的培养条件下，细胞死亡并未被阻止，这表明DUT-M仅保护正在分裂的细胞。通过证明dUTPase蛋白水平的增加足以使培养的C2C12小鼠骨骼肌成肌细胞对H₂O₂的抗性增强，证实了DUT-M的抗凋亡功能。鉴于dUTPase的功能是降低dUTP的水平，我们的结果有力地支持了dUTP作为一种促凋亡第二信使的新作用，其与ROS和神经酰胺类似。
