P53 MUTATIONS INCREASE RESISTANCE TO IONIZING-RADIATION
P53 MUTATIONS INCREASE RESISTANCE TO IONIZING-RADIATION
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DOI：
10.1073/pnas.90.12.5742
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发表时间：
1993-06-15
影响因子：
11.1
通讯作者：
BERNSTEIN, A
中科院分区：
文献类型：
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作者：
LEE, JM;BERNSTEIN, A
不同来源的小鼠和人类肿瘤经常具有 p53 基因的体细胞获得性突变或重排，或者丢失了该基因的一个或两个拷贝。尽管野生型 p53 蛋白被认为具有肿瘤抑制基因的功能，但目前尚不清楚 p53 突变如何导致肿瘤发展。野生型 p53 被认为在 DNA 修复中发挥作用，这表明 p53 突变体的表达可能会改变细胞对伽马辐射引起的 DNA 损伤的抵抗力。此外，p53被认为在辐射后充当细胞周期检查点，这也表明突变的p53可能会改变细胞对辐射的增殖反应。我们使用表达 p53 两个突变等位基因之一的转基因小鼠来测试这一预测。我们的结果表明，小鼠 p53 基因的两种突变体的表达显着增加了多种造血细胞谱系对伽马辐射的细胞抵抗力。这些观察结果提供了直接证据，表明 p53 突变通过增加 DNA 修复过程或可能通过增加细胞对 DNA 损伤的耐受性来影响细胞对 DNA 损伤的反应。 p53 突变与放射抗性增加的关联表明 p53 基因的改变可能导致致癌转化的可能机制。
Mouse and human tumors of diverse origin frequently have somatically acquired mutations or rearrangements of the p53 gene, or they have lost one or both copies of the gene. Although wild-type p53 protein is believed to function as a tumor-suppressor gene, it is as yet unclear how p53 mutations lead to neoplastic development. Wild-type p53 has been postulated to play a role in DNA repair, suggesting that expression of mutant forms of p53 might alter cellular resistance to the DNA damage caused by gamma radiation. Moreover, p53 is thought to function as a cell cycle checkpoint after irradiation, also suggesting that mutant p53 might change the cellular proliferative response to radiation. We have used transgenic mice expressing one of two mutant alleles of p53 to test this prediction. Our results show that expression of both mutant variants of the mouse p53 gene significantly increases the cellular resistance of a variety of hematopoietic cell lineages to gamma radiation. These observations provide direct evidence that p53 mutations affect the cellular response to DNA damage, either by increasing DNA repair processes or, possibly, by increasing cellular tolerance to DNA damage. The association of p53 mutations with increased radioresistance suggests possible mechanisms through which alterations in the p53 gene might lead to oncogenic transformation.