The role of the Ataxia telangiectasia gene in the p53, WAF1/CIP1(p21)- and GADD45-mediated response to DNA damage produced by ionising radiation.
The role of the Ataxia telangiectasia gene in the p53, WAF1/CIP1(p21)- and GADD45-mediated response to DNA damage produced by ionising radiation.
复制标题
共济失调毛细血管扩张基因在 p53、WAF1/CIP1(p21) 和 GADD45 介导的电离辐射 DNA 损伤反应中的作用。
作者：
M. Artuso;A. Esteve;H. Brésil;M. Vuillaume;Janet Hall
在毛细血管扩张性共济失调(AT)细胞系中检测了肿瘤抑制基因p53的诱导反应。AT细胞系是一种常染色体隐性遗传病，具有多种临床和生物学异常，包括对电离辐射的敏感性。照射后6h，8个AT细胞系的P53诱导明显延迟和降低，与对照组相比未观察到剂量效应。经P53转录激活的两个基因WAF1/CIP1(P21)和GADD45mRNA在AT细胞株中的表达也明显降低。相反，烷化剂甲基甲烷磺酸盐(25和100微克·ml~(-1))对两种细胞的P53蛋白、WAF1/CIP1(P21)和GADD45基因表达的影响相似。在所研究的AT细胞系中，未发现EBNA-5的表达或p53基因(外显子4至8)的突变。EBNA-5是一种EBV编码的核抗原，已被证明与P53结合。因此，AT基因产物似乎涉及P53、GADD45和WAF1/CIP1(P21)的上游，以信号传递电离辐射产生的链断裂的存在，作为回应，这种缺陷导致了在这种疾病中观察到的高癌症风险和辐射敏感性。
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.