Nijmegen breakage syndrome cells fail to induce the p53-mediated DNA damage response following exposure to ionizing radiation
Nijmegen breakage syndrome cells fail to induce the p53-mediated DNA damage response following exposure to ionizing radiation
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奈梅亨断裂综合征细胞在暴露于电离辐射后无法诱导 p53 介导的 DNA 损伤反应
DOI：
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发表时间：
1997
影响因子：
5.3
通讯作者：
Janet Hall
中科院分区：
文献类型：
--
作者：
Wim Jongmans;Michèle Vuillaume;Krystyna H. Chrzanowska;Dominique Smeets;Karl Sperling;Janet Hall
在原代成纤维细胞培养物和来自奈亨破裂综合征（NBS）患者的Epstein-Barr病毒转化淋巴母细胞样细胞系中，对p53介导的通路的功能进行了评估，该通路在DNA损伤反应中被激活。这种常染色体隐性遗传病的特点是小头畸形、生长和智力迟钝、染色体不稳定、放射敏感性和高癌症发病率。最近将NBS基因定位到染色体8q21上，表明NBS在遗传上不同于共济失调毛细血管扩张症（AT）。放疗后（5 Gy） 4小时内，与正常培养相比，所有NBS成纤维细胞培养和淋巴母细胞样细胞系中p53蛋白水平的变化显著降低和延迟。p21(WAF1/CIP1) mRNA的转录激活在12个NBS成纤维细胞培养中也较低。与p53功能缺失一致，暴露于电离辐射的NBS细胞在G1-S期表现出异常的细胞周期停滞，并在G2期延长细胞积累。相比之下，暴露于烷基化剂甲基甲磺酸导致两种细胞类型中p53和p21(WAF1/CIP1) mRNA的相似增加。ATM基因转录物在NBS和正常细胞中表达水平相似，而在at纯合子细胞中表达水平明显降低。这些结果表明，ATM基因产物在电离辐射产生的细胞损伤信号传导中不能替代NBS基因，两者都参与了p53的激活。p53介导的次优反应可能导致NBS患者的高癌症风险和放射敏感性。
The functionality of the p53-mediated pathway, activated in response to DNA damage, has been assessed in primary fibroblast cell cultures and Epstein-Barr virus-transformed lymphoblastoid cell lines derived from Nijmegen breakage syndrome (NBS) patients. This autosomal recessive disease is characterized by microcephaly, growth and mental retardation, chromosomal instability, radiosensitivity, and high cancer incidence. The recent mapping of the NBS gene to chromosome 8q21 demonstrates that NBS is genetically distinct from ataxia telangiectasia (AT). Changes in p53 protein levels were significantly reduced and delayed in all the NBS fibroblast cell cultures and lymphoblastoid cell lines examined compared to normal cultures over a 4-h period postirradiation (5 Gy). The transcriptional activation of p21(WAF1/CIP1) mRNA was also lower in 12 NBS fibroblast cultures examined. In agreement with an abrogated p53 function, NBS cells exposed to ionizing radiation show an abnormal cell cycle arrest at G1-S and a prolonged accumulation of cells in the G2 phase. In contrast, exposure to the alkylating agent methyl methanesulfonate results in similar increases of p53 and p21(WAF1/CIP1) mRNA in both cell types. The ATM gene transcript was found to be expressed at similar levels in NBS and normal cells, whereas it was strongly reduced in the AT homozygote cells examined. These results suggest that the ATM gene product cannot substitute for that of the NBS gene in the signaling of cellular damage produced by ionizing radiation and that both are involved in the activation of p53. The suboptimal p53-mediated response could contribute to the high cancer risk and radiosensitivity seen in NBS patients.
影响因子：
3.5
作者：
Gilad, S;Khosravi, R;BarShira, A
通讯作者：
BarShira, A
ATM 基因产物磷酸化 I kappa B-alpha。
影响因子：
11.2
作者：
Jung,M;Kondratyev,A;Lee,SA;Dimtchev,A;Dritschilo,A
通讯作者：
Dritschilo,A
影响因子：
56.9
作者：
SAVITSKY, K;BARSHIRA, A;SHILOH, Y
通讯作者：
SHILOH, Y