Integrity of zinc finger motifs in PML protein is necessary for inducing its degradation by antimony
Integrity of zinc finger motifs in PML protein is necessary for inducing its degradation by antimony
复制标题
PML 蛋白中锌指基序的完整性对于诱导其被锑降解是必要的
作者：
Chang Yang;Rui Hao;Yong Fei Lan;Ye Jia Chen;Chao Wang;Na Bu;Qian Qian Wang;Liaqat Hussain;Li Ya Ma;Yasen Maimaitiyiming;Xiao Yang Lu;Hua Naranm;ura
锑（Sb）与砷（as）在元素周期表中属于同一族，两者具有相似的特征。然而，与三氧化二砷（As2O3）不同，Sb2O3（SbIII）没有甲基化能力。在本研究中，我们检测了sbiion对NB4细胞的影响，发现锑可以诱导PML-RARα融合蛋白降解，PML-NBs重组，并以低细胞毒性诱导NB4细胞分化。另一方面，PML蛋白中的锌指基序被认为是砷诱导PML- rar α蛋白降解的关键靶点结合位点。有趣的是，在NB4细胞中，经菲罗啉（即锌离子螯合剂）预处理后，锑和砷失去了对PML-RARα融合蛋白的降解能力，这表明PML-RARα融合蛋白中锌指基序的完整性是诱导PML-RARα融合蛋白被锑和砷降解的基本条件。此外，我们发现sbiii不会诱导突变体PML（例如A126V和L218P）溶解度变化和降解，类似于As2O3。相比之下，我们发现有机锑化合物苯斯蒂宾氧化物（PSO）可以诱导突变体PML蛋白降解。总之，我们的研究结果表明，sbii也可能是一种治疗急性早幼粒细胞白血病的有希望的药物，就像As2O3一样。
Antimony (Sb) belongs to the same group as arsenic (As) in the periodic table, and both share similar characteristics. However, Sb2O3(SbIII) has no methylation capacity, unlike arsenic trioxide (As2O3). In the present study, we determined the effect of SbIIIon NB4 cells and found that antimony could induce PML-RARα fusion protein degradation, reorganization of PML-NBs, and NB4 cell differentiation with low cytotoxicity. On the other hand, zinc finger motifs in PML protein are considered to be a key target binding site for arsenic-induced PML-RARα protein degradation. Interestingly, antimony and arsenic lost their ability to degrade PML-RARα fusion protein in NB4 cells following pretreatment with phenanthroline (i.e., chelator of zinc ions), indicating that the integrity of zinc finger motifs in PML-RARα fusion protein is a fundamental condition for inducing the protein's degradation by antimony and arsenic. Moreover, we found that SbIIIcould not induce mutant PML (e.g., A126V and L218P) solubility change and degradation, similar to As2O3. In contrast, we found that the organic antimony compound phenylstibine oxide (PSO) could induce mutant PML protein degradation. In conclusion, our results indicate that SbIIImight also be a promising agent to treat acute promyelocytic leukemia, in the same manner as As2O3.