Mutant p53 gain of function: differential effects of different p53 mutants on resistance of cultured cells to chemotherapy
Mutant p53 gain of function: differential effects of different p53 mutants on resistance of cultured cells to chemotherapy
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DOI：
10.1038/sj.onc.1202314
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发表时间：
1999-01-14
期刊：
影响因子：
8
通讯作者：
Oren, M
中科院分区：
文献类型：
--
作者：
Blandino, G;Levine, AJ;Oren, M
越来越多的研究表明，细胞中p53突变的性质可以影响细胞特性、对治疗的临床反应和肿瘤的预后。为了探索这些观察结果的细胞基础，设计实验以比较相同细胞群中具有和不具有p53突变的细胞的性质。为此，将各种肿瘤衍生的人p53突变体引入p53缺失的H1299肺腺癌细胞中。克隆形成存活实验表明，p53 His 175突变体的过表达细胞，而不是p53 His 273突变体，优先从依托泊苷处理中恢复。此外，p53 His 175和p53 His 179显著降低依托泊苷诱导的凋亡率，而p53 His 273和p53 Trp 248具有温和得多的保护作用。相反，p53 His 175和p53 His 273对顺铂的细胞反应产生非常相似的作用;两者都赋予对低浓度药物（2.5 μ g/ml）的增加的抗性，但对高浓度（10 μ g/ml）根本没有保护作用。因此，特定的p53突变体可能赋予肿瘤细胞在化疗期间的选择性存活优势。这些发现定义了一种新型的突变体p53选择性功能获得，其可能损害癌症化疗的功效。
Many tumors overexpress mutant forms of p53, A growing number of studies suggest that the nature of a p53 mutation in a cell can impact upon cellular properties, clinical responses to therapy and prognosis of a tumor. To explore the cellular basis of these observations, experiments were designed to compare the properties of cells with and without p53 mutations within the same cell population. To that end, various tumor-derived human p53 mutants,were introduced into p53-null H1299 lung adenocarcinoma cells. Clonogenic survival assays revealed that cells overexpressing the p53His175 mutant, but not the p53His273 mutant, recover preferentially from etoposide treatment, Moreover, p53His175 as well as p53His179 reduced substantially the rate of etoposide-induced apoptosis, whereas p53His273 and p53Trp248 had a much milder protective effect. In contrast, p53His175 and p53His273 exerted, very similar effects on the cellular response to cisplatin; both conferred increased resistance to low concentrations of the drug (2.5 mu g/ml), but did not protect at all against high concentrations (10 mu g/ml). Hence particular p53 mutants may confer upon tumor cells a selective survival advantage during chemotherapy, These findings define a new type of mutant p53 selective gain of function which may compromise the efficacy of cancer chemotherapy.