Pedrote Murilo M, Motta Michelle F, Ferretti Giulia D S, Norberto Douglas R, Spohr Tania C L S, Lima Flavia R S, Gratton Enrico, Silva Jerson L, de Oliveira Guilherme A P
Institute of Medical Biochemistry Leopoldo de Meis, National Institute of Science and Technology for Structural Biology and Bioimaging, National Center of Nuclear Magnetic Resonance Jiri Jonas, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro 21941-901, Brazil.
Universidade Federal do ABC, Centro de Ciências Naturais e Humanas. Av. dos Estados, 5001 Sta. Terezinha, Santo André, São Paulo 21941-590, Brazil.
iScience. 2020 Feb 21;23(2):100820. doi: 10.1016/j.isci.2020.100820. Epub 2020 Jan 8.
Tumor-associated p53 mutations endow cells with malignant phenotypes, including chemoresistance. Amyloid-like oligomers of mutant p53 transform this tumor suppressor into an oncogene. However, the composition and distribution of mutant p53 oligomers are unknown and the mechanism involved in the conversion is sparse. Here, we report accumulation of a p53 mutant within amyloid-like p53 oligomers in glioblastoma-derived cells presenting a chemoresistant gain-of-function phenotype. Statistical analysis from fluorescence fluctuation spectroscopy, pressure-induced measurements, and thioflavin T kinetics demonstrates the distribution of oligomers larger than the active tetrameric form of p53 in the nuclei of living cells and the destabilization of native-drifted p53 species that become amyloid. Collectively, these results provide insights into the role of amyloid-like mutant p53 oligomers in the chemoresistance phenotype of malignant and invasive brain tumors and shed light on therapeutic options to avert cancer.
肿瘤相关的p53突变赋予细胞恶性表型，包括化学抗性。突变型p53的淀粉样寡聚体将这种肿瘤抑制因子转化为致癌基因。然而，突变型p53寡聚体的组成和分布尚不清楚，且参与这种转化的机制也鲜为人知。在此，我们报告了在呈现化学抗性功能获得表型的胶质母细胞瘤衍生细胞中，一种p53突变体在淀粉样p53寡聚体内的积累。来自荧光涨落光谱、压力诱导测量和硫黄素T动力学的统计分析表明，大于p53活性四聚体形式的寡聚体分布在活细胞核中，并且天然漂移的p53物种会不稳定并变成淀粉样蛋白。总的来说，这些结果为淀粉样突变型p53寡聚体在恶性侵袭性脑肿瘤的化学抗性表型中的作用提供了见解，并为预防癌症的治疗选择提供了线索。
