Rescue of non-sense mutated p53 tumor suppressor gene by aminoglycosides.
Rescue of non-sense mutated p53 tumor suppressor gene by aminoglycosides.
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DOI：
10.1093/nar/gkq1277
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发表时间：
2011-04
影响因子：
14.9
通讯作者：
Bidou L
中科院分区：
文献类型：
--
作者：
Floquet C;Deforges J;Rousset JP;Bidou L
基于突变的治疗是遗传医学的新发展，其中突变的性质决定了治疗策略。最近人们的兴趣集中在由提前终止密码子（PTC）引起的疾病上。诱导这些 PTC 通读的药物可恢复全长蛋白质的产生。在这项研究中，我们探索了使用氨基糖苷类抗生素诱导携带 PTC 的基因产生全长功能性 p53 蛋白的可能性。我们鉴定出含有 PTC 的人类癌细胞系，在氨基糖苷类存在的情况下获得了高水平的通读。使用这些细胞，我们证明氨基糖苷类处理可以稳定突变体 mRNA，否则突变体 mRNA 会因无义介导的衰变而被降解，从而产生功能性全长 p53 蛋白。最后，我们发现氨基糖苷类治疗会降低癌细胞的活力，特别是在存在无义突变的 p53 基因的情况下。这些结果为开发与肿瘤抑制基因无义突变相关的癌症的有希望的治疗方法提供了可能性。他们表明，旨在诱导终止密码子通读的分子可用于抑制肿瘤生长，并为开发新的个性化策略提供合理的基础，从而使现有的癌症治疗方法多样化。
Mutation-based treatments are a new development in genetic medicine, in which the nature of the mutation dictates the therapeutic strategy. Interest has recently focused on diseases caused by premature termination codons (PTCs). Drugs inducing the readthrough of these PTCs restore the production of a full-length protein. In this study, we explored the possibility of using aminoglycoside antibiotics to induce the production of a full-length functional p53 protein from a gene carrying a PTC. We identified a human cancer cell line containing a PTC, for which high levels of readthrough were obtained in the presence of aminoglycosides. Using these cells, we demonstrated that aminoglycoside treatment stabilized the mutant mRNA, which would otherwise have been degraded by non-sense-mediated decay, resulting in the production of a functional full-length p53 protein. Finally, we showed that aminoglycoside treatment decreased the viability of cancer cells specifically in the presence of nonsense-mutated p53 gene. These results open possibilities of developing promising treatments of cancers linked with non-sense mutations in tumor suppressor genes. They show that molecules designed to induce stop-codon readthrough can be used to inhibit tumor growth and offer a rational basis for developing new personalized strategies that could diversify the existing arsenal of cancer therapies.
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DOI：
10.1164/ajrccm.163.7.2004001
发表时间：
2001-06-01
影响因子：
24.7
作者：
Clancy, JP;Bobök, Z;Bedwell, DM
通讯作者：
Bedwell, DM
影响因子：
14.9
作者：
BURKE, JF;MOGG, AE
通讯作者：
MOGG, AE
影响因子：
11.2
作者：
Malik, Vinod;Rodino-Klapac, Louise R.;Mendell, Jerry R.
通讯作者：
Mendell, Jerry R.
影响因子：
11.4
作者：
Linde, Liat;Kerem, Batsheva
通讯作者：
Kerem, Batsheva
影响因子：
4.5
作者：
Bidou, L;Stahl, G;Farabaugh, PJ
通讯作者：
Farabaugh, PJ