Lavin M F
Queensland Institute of Medical Research, Royal Brisbane Hospital, Brisbane, Australia.
Int J Biochem Cell Biol. 1999 Jul;31(7):735-40. doi: 10.1016/s1357-2725(99)00028-x.
Ataxia-telangiectasia mutated (ATM) is the product of the gene mutated in the human genetic disorder ataxia-telangeictasia (A-T). It is a 370 kDa protein that is a member of the phosphatidyl inositol 3-kinases superfamily. A-T cells and those derived from Atm-/- mice are characterized by hypersensitivity to ionizing radiation and defective cell cycle checkpoints. Defects are observed at all cell cycle checkpoints in A-T cells post-irradiation including the G1/S interface where ATM plays an important role in the activation of the tumour suppressor gene product p53. Activation leads to the induction of p21/WAF1, inhibition of cyclin-dependent kinase activity, failure to phosphorylate key substrates such as the retinoblastoma protein and consequently G1 arrest. ATM also plays an important role in the regulation and surveillance of meiotic progression. Absence of ATM gives rise to a spectrum of defects including immunodeficiency, neurodegeneration, radiosensitivity and cancer predisposition. It is clear that a better definition of the role of ATM in DNA damage recognition, cell cycle control and cell signalling may assist in the treatment of the progressive neurodegeneration in this syndrome.
共济失调毛细血管扩张症突变基因（ATM）是人类遗传性疾病共济失调毛细血管扩张症（A-T）中发生突变的基因的产物。它是一种370 kDa的蛋白质，属于磷脂酰肌醇3激酶超家族成员。A-T细胞以及源自Atm-/-小鼠的细胞的特征是对电离辐射敏感且细胞周期检查点存在缺陷。在照射后的A-T细胞的所有细胞周期检查点均观察到缺陷，包括G1/S界面，在该界面ATM在肿瘤抑制基因产物p53的激活中起重要作用。激活导致p21/WAF1的诱导，抑制细胞周期蛋白依赖性激酶活性，无法磷酸化关键底物（如视网膜母细胞瘤蛋白），从而导致G1期停滞。ATM在减数分裂进程的调节和监测中也起重要作用。ATM的缺失会导致一系列缺陷，包括免疫缺陷、神经退行性变、放射敏感性和癌症易感性。显然，更好地定义ATM在DNA损伤识别、细胞周期控制和细胞信号传导中的作用可能有助于治疗该综合征中的进行性神经退行性变。
