Formichi P, Battisti C, Tripodi S A, Federico A
U.O. Neurometabolic Diseases, Institute of Neurological Sciences, University of Siena, Italy.
Life Sci. 2000 Apr 7;66(20):1893-903. doi: 10.1016/s0024-3205(00)00515-4.
The recently identified ATM gene plays a role in a signal transduction network activating multiple cellular functions in response to DNA damage. An attractive hypothesis is that the ATM protein is involved in a specialized antioxidant system responsible for detoxifying reactive oxygen intermediate and that the absence or dysfunction of this protein in AT cells would render them less capable of dealing with oxidative stress. In order to investigate the role of the ATM gene in cell cycle control and programmed cell death, Lymphoblastoid cell lines derived from four Ataxia-Telangiectasia (AT) patients and six controls have been analyzed. All cell lines were incubated with 2-deoxy-D-ribose (dRib), a reducing sugar that induces apoptosis through oxidative stress. The result showed an impaired response to dRib-induced apoptosis in AT cells, as well as a defect of cellular cycle arrest in G1/S phase and a normal expression of p53 protein. This indicate that the kinase activity of ATM gene product plays a very important role in the cellular response to oxidative stress. In conclusion the altered response of AT cells to oxidative stress and particularly their resistance to apoptotic cell death, could explain the high predisposition of these cells to progress toward malignant transformation.
最近发现的ATM基因在一个信号转导网络中发挥作用，该网络可激活多种细胞功能以应对DNA损伤。一个引人注目的假说是，ATM蛋白参与了一个专门的抗氧化系统，负责清除活性氧中间体，并且AT细胞中该蛋白的缺失或功能障碍会使它们应对氧化应激的能力降低。为了研究ATM基因在细胞周期调控和程序性细胞死亡中的作用，我们分析了来自四名共济失调毛细血管扩张症（AT）患者和六名对照的淋巴母细胞系。所有细胞系都用2-脱氧-D-核糖（dRib）进行孵育，dRib是一种还原糖，可通过氧化应激诱导细胞凋亡。结果显示，AT细胞对dRib诱导的细胞凋亡反应受损，同时在G1/S期存在细胞周期阻滞缺陷以及p53蛋白表达正常。这表明ATM基因产物的激酶活性在细胞对氧化应激的反应中起着非常重要的作用。总之，AT细胞对氧化应激的反应改变，尤其是它们对凋亡性细胞死亡的抗性，可能解释了这些细胞极易发生恶性转化的原因。
