Department of Chemistry, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada.
Inserm UMR_S1113, IRFAC, team Streinth, Strasbourg University, Strasbourg, France.
J Biol Inorg Chem. 2022 Aug;27(4-5):393-403. doi: 10.1007/s00775-022-01939-2. Epub 2022 Apr 30.
Metal ion dysregulation has been implicated in a number of diseases from neurodegeneration to cancer. While defective metal ion transport mechanisms are known to cause specific diseases of genetic origin, the role of metal dysregulation in many diseases has yet to be elucidated due to the complicated function (both good and bad!) of metal ions in the body. A breakdown in metal ion speciation can manifest in several ways from increased reactive oxygen species (ROS) generation to an increase in protein misfolding and aggregation. In this review, we will discuss the role of Zn in the proper function of the p53 protein in cancer. The p53 protein plays a critical role in the prevention of genome mutations via initiation of apoptosis, DNA repair, cell cycle arrest, anti-angiogenesis, and senescence pathways to avoid propagation of damaged cells. p53 is the most frequently mutated protein in cancer and almost all cancers exhibit malfunction along the p53 pathway. Thus, there has been considerable effort dedicated to restoring normal p53 expression and activity to mutant p53. This includes understanding the relative populations of the Zn-bound and Zn-free p53 in wild-type and mutant forms, and the development of metallochaperones to re-populate the Zn binding site to restore mutant p53 activity. Parallels will be made to the development of multifunctional metal binding agents for modulating the aggregation of the amyloid-beta peptide in Alzheimer's Disease (AD).
金属离子失调与许多疾病有关，从神经退行性疾病到癌症。虽然已知金属离子转运机制缺陷会导致特定的遗传来源疾病，但由于金属离子在体内的复杂功能（既有好处也有坏处！），金属失调在许多疾病中的作用仍有待阐明。金属离子形态的破坏可能以多种方式表现出来，从增加活性氧（ROS）的产生到增加蛋白质错误折叠和聚集。在这篇综述中，我们将讨论 Zn 在癌症中 p53 蛋白正常功能中的作用。p53 蛋白通过启动细胞凋亡、DNA 修复、细胞周期阻滞、抗血管生成和衰老途径，在防止基因组突变方面发挥着关键作用，以避免受损细胞的传播。p53 是癌症中突变最频繁的蛋白，几乎所有癌症都表现出 p53 途径的功能障碍。因此，人们做出了相当大的努力来恢复突变型 p53 的正常 p53 表达和活性。这包括了解 Zn 结合和 Zn 游离 p53 在野生型和突变型中的相对群体，以及开发金属伴侣来重新填充 Zn 结合位点以恢复突变型 p53 活性。将与多功能金属结合剂的开发进行对比，以调节阿尔茨海默病（AD）中淀粉样β肽的聚集。
