Shackelford R E, Innes C L, Sieber S O, Heinloth A N, Leadon S A, Paules R S
Growth Control and Cancer Group, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
J Biol Chem. 2001 Jun 15;276(24):21951-9. doi: 10.1074/jbc.M011303200. Epub 2001 Apr 4.
Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by neuronal degeneration accompanied by ataxia, telangiectasias, acute cancer predisposition, and sensitivity to ionizing radiation (IR). Cells from individuals with AT show unusual sensitivity to IR, severely attenuated cell cycle checkpoint functions, and poor p53 induction in response to IR compared with normal human fibroblasts (NHFs). The gene mutated in AT (ATM) has been cloned, and its product, pATM, has IR-inducible kinase activity. The AT phenotype has been suggested to be a consequence, at least in part, of an inability to respond appropriately to oxidative damage. To test this hypothesis, we examined the ability of NHFs and AT dermal fibroblasts to respond to t-butyl hydroperoxide and IR treatment. AT fibroblasts exhibit, in comparison to NHFs, increased sensitivity to the toxicity of t-butyl hydroperoxide, as measured by colony-forming efficiency assays. Unlike NHFs, AT fibroblasts fail to show G(1) and G(2) phase checkpoint functions or to induce p53 in response to t-butyl hydroperoxide. Treatment of NHFs with t-butyl hydroperoxide activates pATM-associated kinase activity. Our results indicate that pATM is involved in responding to certain aspects of oxidative damage and in signaling this information to downstream effectors of the cell cycle checkpoint functions. Our data further suggest that some of the pathologies seen in AT could arise as a consequence of an inability to respond normally to oxidative damage.
共济失调毛细血管扩张症（AT）是一种常染色体隐性疾病，其特征为神经元变性，并伴有共济失调、毛细血管扩张、急性癌症易感性以及对电离辐射（IR）敏感。与正常人成纤维细胞（NHF）相比，AT患者的细胞对IR表现出异常敏感性，细胞周期检查点功能严重减弱，且对IR刺激的p53诱导反应较差。AT相关的突变基因（ATM）已被克隆，其产物pATM具有IR诱导的激酶活性。有人提出，AT表型至少部分是由于无法对氧化损伤做出适当反应所致。为了验证这一假设，我们检测了NHF和AT皮肤成纤维细胞对叔丁基过氧化氢和IR处理的反应能力。通过集落形成效率测定发现，与NHF相比，AT成纤维细胞对叔丁基过氧化氢的毒性更敏感。与NHF不同，AT成纤维细胞在叔丁基过氧化氢刺激下无法表现出G(1)和G(2)期检查点功能，也无法诱导p53。用叔丁基过氧化氢处理NHF可激活与pATM相关的激酶活性。我们的结果表明，pATM参与了对氧化损伤某些方面的反应，并将此信息传递给细胞周期检查点功能的下游效应器。我们的数据进一步表明，AT中出现的一些病理情况可能是由于无法正常应对氧化损伤所致。
