Genetic selection of intragenic suppressor mutations that reverse the effect of common p53 cancer mutations
Genetic selection of intragenic suppressor mutations that reverse the effect of common p53 cancer mutations
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DOI：
10.1093/emboj/17.7.1847
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发表时间：
1998-04-01
期刊：
影响因子：
11.4
通讯作者：
Boeke, JD
中科院分区：
文献类型：
--
作者：
Brachmann, RK;Yu, KX;Boeke, JD
一些证据表明，野生型肿瘤抑制基因p53在人类癌症中的存在与成功的抗癌治疗有很好的相关性。因此，将野生型p53功能恢复到失去它的癌细胞可能会改善治疗结果。使用系统的酵母遗传方法，我们选择了第二位点抑制突变，这些突变可以克服人类细胞中常见的p53癌症突变的有害影响。我们确定了V143A、G245S和R249S癌症突变的几个抑制突变。这些抑制子突变的有益效果通过哺乳动物报告基因和细胞凋亡检测得到了证实。进一步的实验表明，这些抑制子突变可以覆盖额外的p53癌症突变。这种抑制突变的机制可以通过结构研究来阐明，最终导致发现能够稳定p53突变的小分子的框架。
Several lines of evidence suggest that the presence of the wild-type tumor suppressor gene p53 in human cancers correlates well with successful anti-cancer therapy. Restoration of wild-type p53 function to cancer cells that have lost it might therefore improve treatment outcomes. Using a systematic yeast genetic approach, we selected second-site suppressor mutations that can overcome the deleterious effects of common p53 cancer mutations in human cells. We identified several suppressor mutations for the V143A, G245S and R249S cancer mutations. The beneficial effects of these suppressor mutations were demonstrated using mammalian reporter gene and apoptosis assays. Further experiments showed that these suppressor mutations could override additional p53 cancer mutations. The mechanisms of such suppressor mutations can be elucidated by structural studies, ultimately leading to a framework for the discovery of small molecules able to stabilize p53 mutants.