Johnson Adam J, Zaman Mohammad S, Veljanoski Filip, Phrakaysone Alex A, Li Suhua, O'Doherty Patrick J, Petersingham Gayani, Perrone Gabriel G, Molloy Mark P, Wu Ming J
School of Science and Health, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia.
College of Life Sciences, Southwest Forestry University, 300 Bailong Road, Kunming 650024, Yunnan Province, P. R. China.
Metallomics. 2017 Mar 22;9(3):301-308. doi: 10.1039/c6mt00230g.
Metal ions, biologically essential or toxic, are present in the surrounding environment of living organisms. Understanding their uptake, homeostasis or detoxification is critical in cell biology and human health. In this study, we investigated the role of protein kinase CK2 in metal toxicity using gene deletion strains of Saccharomyces cerevisiae against a panel of six metal ions. The deletion of CKA2, the yeast orthologue of mammalian CK2α', leads to a pronounced resistant phenotype against Zn and Al, whilst the deletion of CKB1 or CKB2 results in tolerance to Cr and As. The individual deletion mutants of CK2 subunits (CKA1, CKA2, CKB1 and CKB2) did not have any benefit against Co and Cd. The metal ion content in the treated cells was then measured by inductively coupled plasma mass spectrometry. Two contrasting findings were obtained for the CKA2 deletion mutant (cka2Δ) against Al or Zn. Upon exposure to Al, cka2Δ had markedly lower Al content than the wild type and other CK2 mutants, congruous to the resistant phenotype of cka2Δ against Al, indicating that CKA2 is responsible for Al uptake. Upon zinc exposure the same mutant showed similar Zn content to the wild type and cka1Δ. Strikingly, the selective inhibitor of CK2 TBB (4,5,6,7-tetrabromo-1H-benzotriazole) abolished the resistant phenotype of cka2Δ against Zn. Hence, the CK2 subunit CKA1 plays a key role in Zn sequestration of the cell. Given that both zinc and CK2 are implicated in cancer development, the findings herein are of significance to cancer research and anticancer drug development.
金属离子，无论是具有生物学重要性还是毒性，都存在于生物体的周围环境中。了解它们的摄取、稳态或解毒过程对于细胞生物学和人类健康至关重要。在本研究中，我们使用酿酒酵母的基因缺失菌株，针对六种金属离子，研究了蛋白激酶CK2在金属毒性中的作用。哺乳动物CK2α'的酵母同源物CKA2的缺失，导致对锌和铝具有明显的抗性表型，而CKB1或CKB2的缺失则导致对铬和砷具有耐受性。CK2亚基（CKA1、CKA2、CKB1和CKB2）的单个缺失突变体对钴和镉没有任何抗性。然后通过电感耦合等离子体质谱法测量处理后细胞中的金属离子含量。对于CKA2缺失突变体（cka2Δ）针对铝或锌的情况，获得了两个截然不同的发现。暴露于铝时，cka2Δ的铝含量明显低于野生型和其他CK2突变体，这与cka2Δ对铝的抗性表型一致，表明CKA2负责铝的摄取。暴露于锌时，相同的突变体显示出与野生型和cka1Δ相似的锌含量。令人惊讶的是，CK2的选择性抑制剂TBB（4,5,6,7-四溴-1H-苯并三唑）消除了cka2Δ对锌的抗性表型。因此，CK2亚基CKA1在细胞的锌螯合中起关键作用。鉴于锌和CK2都与癌症发展有关，本文的研究结果对癌症研究和抗癌药物开发具有重要意义。
