Stability Change of Tetrameric Structure of Tumor Suppressor Protein p53 in Mutation and Evolution, and Threshold for Loss of Tumor Suppressor Activity in Terms of Disruption of the Tetrameric Structure.

肿瘤抑制因子p53诱导细胞周期阻滞和细胞凋亡以响应基因毒性应激。大约50%的人类肿瘤有TP53基因突变；大多数是误义基因，可能会降低p53的肿瘤抑制活性。在这项研究中，我们探讨了已知肿瘤来源的错义突变对p53的稳定性和低聚结构的影响。结果表明，就p53的四聚体结构破坏而言，肿瘤抑制活性丧失的阈值可能非常低。我们开发了一种可以增加突变体R337H四聚体稳定性的一杯芳烃衍生物，该突变体是在Li-Fraumeni综合征中发现的，这是一种以家族性早发性多发性肿瘤集群为特征的遗传性疾病。我们还发现，四聚体的稳定性随着脊椎动物：鱼-两栖-鸟和哺乳动物的进化而增加。结果表明，四聚结构域的折叠会严格控制其功能表达。

The tumor suppressor p53 induces cell cycle arrest and apoptosis in response to genotoxic stress. About 50% of human tumors have TP53 gene mutations ; most are missense ones that presumably lower p53's tumor suppressor activity. In this study, we explored the effects of known tumor-derived missense mutations on the stability and oligomeric structure of p53. The results suggested that threshold for loss of tumor suppressor activity in terms of the disruption of p53's tetrameric structure could be extremely low. We developed a calixarene derivative that could increase the tetrameric stability of the mutant R337H, which is found in Li-Fraumeni syndrome, a hereditary disorder characterized by familial clusters of early-onset multiple tumors. We also showed that the tetramer stability increased through the evolution of vertebrates : fish-amphibian-bird and mammals. The results suggested that the folding of the tetramerization domain would tightly control its functional expression.