Artuso M, Esteve A, Brésil H, Vuillaume M, Hall J
Unit of Mechanisms of Carcinogenesis, International Agency for Research on Cancer, Lyon, France.
Oncogene. 1995 Oct 19;11(8):1427-35.
The inducible response of the tumour suppressor gene p53 has been examined following exposure to DNA-damaging agents in Ataxia telangiectasia (AT) cell lines, an autosomal recessive disorder with multiple clinical and biological abnormalities including sensitivity to ionising radiation. The p53 induction was significantly delayed and reduced in the 8 AT cell lines examined over the 6 h following irradiation with no dose response in p53 induction being observed compared to control cells. The increase of WAF1/CIP1(p21) and GADD45 mRNA, two genes transcriptionally activated by p53, was also reduced in the AT cell lines after such treatment. In contrast, the increase in p53 protein, WAF1/CIP1(p21) and GADD45 mRNA expression following exposure to the alkylating agent methylmethane sulphonate (25 and 100 micrograms ml-1) was similar in both cell types. No alterations in the expression of EBNA-5, an EBV-encoded nuclear antigen which has been shown to bind p53 or mutations in the p53 gene (exons 4 to 8) were found in the AT cell lines studied. The AT gene product would thus appear to be involved upstream of p53, GADD45 and WAF1/CIP1 (p21) in the signalling of the presence of strand breaks produced by ionising radiation, with this defect in response contributing to the high cancer risk and radiosensitivity observed in this disorder.
在共济失调毛细血管扩张症（AT）细胞系中，研究了暴露于DNA损伤剂后肿瘤抑制基因p53的诱导反应。AT是一种常染色体隐性疾病，具有多种临床和生物学异常，包括对电离辐射敏感。在所检测的8个AT细胞系中，照射后6小时内p53的诱导明显延迟且减弱，与对照细胞相比，未观察到p53诱导的剂量反应。在这种处理后，p53转录激活的两个基因WAF1/CIP1（p21）和GADD45 mRNA的增加在AT细胞系中也减少。相反，暴露于烷化剂甲磺酸甲酯（25和100微克/毫升）后，两种细胞类型中p53蛋白、WAF1/CIP1（p21）和GADD45 mRNA表达的增加相似。在所研究的AT细胞系中，未发现EBV编码的核抗原EBNA-5的表达改变，EBNA-5已被证明可结合p53，也未发现p53基因（外显子4至8）的突变。因此，AT基因产物似乎在电离辐射产生的链断裂信号传导中参与p53、GADD45和WAF1/CIP1（p21）的上游，这种反应缺陷导致了该疾病中观察到的高癌症风险和放射敏感性。
