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.

肿瘤抑制基因P53诱导细胞周期停滞和细胞凋亡，以响应基因毒性应激。大约50%的人类肿瘤有TP53基因突变；大多数是错义突变，可能降低了P53‘S的肿瘤抑制活性。在这项研究中，我们探索了已知的肿瘤来源错义突变对P53稳定性和寡聚体结构的影响。结果表明，以P53‘S四聚体结构的破坏为基础的肿瘤抑制活性丧失的阈值可能非常低。我们开发了一种杯芳烃衍生物，可以增加突变的R337H的四聚体稳定性，该突变在Li-Fraumeni综合征中发现，Li-Fraumeni综合征是一种以早发性多发性肿瘤家族性聚集性为特征的遗传性疾病。我们还表明，通过脊椎动物：鱼-两栖动物-鸟类和哺乳动物的进化，四聚体的稳定性增加了。结果表明，四聚结构域的折叠将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.