Acquisition of p53 mutations in response to the non-genotoxic p53 activator Nutlin-3.
Acquisition of p53 mutations in response to the non-genotoxic p53 activator Nutlin-3.
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DOI：
10.1038/onc.2011.185
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发表时间：
2011-11-17
期刊：
影响因子：
8
通讯作者：
Maki, C. G.
中科院分区：
文献类型：
--
作者：
Aziz, M. H.;Shen, H.;Maki, C. G.
关键词：
野生型p53是一种应激反应性肿瘤抑制因子和有效的生长抑制剂。基因毒性应激（如电离和紫外线辐射或化疗药物治疗）可以激活p53，但也会诱导p53基因突变，从而选择p53突变的细胞。Nutlin-3a （Nutlin）是一种以非基因毒性方式激活p53的临床前药物。Nutlin占据MDM2的p53结合口袋，通过阻断p53-MDM2相互作用激活p53。由于Nutlin既不直接结合p53，也不引入DNA损伤，我们假设Nutlin不会诱导p53突变，因此不会选择p53突变的细胞。为了验证这一点，扩增SJSA-1 （p53野生型）癌细胞群，使其在反复暴露于Nutlin中存活下来，并分离出单个克隆。1组克隆对nutlin诱导的细胞凋亡有抗性，但仍发生生长停滞。令人惊讶的是，虽然一些第1组克隆保留了野生型p53，但其他克隆获得了杂合型p53突变。第1组克隆的凋亡抵抗与PUMA诱导减少和caspase 3/7激活减少有关。2组克隆对Nutlin诱导的细胞凋亡和生长停滞均有抗性。第2组克隆在p53 dna结合域获得突变，仅表达Nutlin诱导的突变p53s，但不能结合P21和PUMA基因启动子，也不能激活转录。这些结果表明，非基因毒性p53激活（例如通过Nutlin治疗）可以导致p53体细胞突变的获得和p53突变细胞的选择。这些发现对Nutlin和其他小分子MDM2拮抗剂的潜在临床应用具有启示意义。
Wild-type p53 is a stress-responsive tumor suppressor and potent growth inhibitor. Genotoxic stresses (e.g. ionizing and UV radiation or chemotherapeutic drug treatment) can activate p53, but also induce mutations in the P53 gene and thus select for p53-mutated cells. Nutlin-3a (Nutlin) is pre-clinical drug that activates p53 in a non-genotoxic fashion. Nutlin occupies the p53-binding pocket of MDM2, activating p53 by blocking the p53-MDM2 interaction. Because Nutlin neither binds p53 directly nor introduces DNA damage, we hypothesized Nutlin would not induce P53 mutations and therefore not select for p53-mutated cells. To test this, populations of SJSA-1 (p53 wild-type) cancer cells were expanded that survived repeated Nutlin exposures, and individual clones were isolated. Group 1 clones were resistant to Nutlin-induced apoptosis, but still underwent growth-arrest. Surprisingly, while some Group 1 clones retained wild-type p53, others acquired a heterozygous p53 mutation. Apoptosis resistance in Group 1 clones was associated with decreased PUMA induction and decreased caspase 3/7 activation. Group 2 clones were resistant to both apoptosis and growth-arrest induced by Nutlin. Group 2 clones had acquired mutations in the p53 DNA-binding domain and expressed only mutant p53s that were induced by Nutlin treatment, but were unable to bind the P21 and PUMA gene promoters, and unable to activate transcription. These results demonstrate that non-genotoxic p53 activation (e.g. by Nutlin treatment) can lead to the acquisition of somatic mutations in p53 and select for p53-mutated cells. These findings have implications for the potential clinical use of Nutlin and other small molecule MDM2 antagonists.
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影响因子：
7.3
作者：
Ahmed, Ashour Ahmed;Etemadmoghadam, Dariush;Temple, Jillian;Lynch, Andy G.;Riad, Mohamed;Sharma, Raghwa;Stewart, Colin;Fereday, Sian;Caldas, Carlos;DeFazio, Anna;Bowtell, David;Brenton, James D.
通讯作者：
Brenton, James D.
影响因子：
11.2
作者：
McDermott, U;Longley, DB;Johnston, PG
通讯作者：
Johnston, PG
影响因子：
8
作者：
Mayelzadeh, F.;Martinez, J. D.
通讯作者：
Martinez, J. D.
DOI：
10.1073/pnas.93.16.8390
发表时间：
1996-08-06
影响因子：
11.1
作者：
Pietenpol, JA;Lengauer, C;Vogelstein, B
通讯作者：
Vogelstein, B
影响因子：
64.5
作者：
MILNER, J;MEDCALF, EA
通讯作者：
MEDCALF, EA