Waller Zoë A E, Howell Lesley A, Macdonald Colin J, O'Connell Maria A, Searcey Mark
School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK.
School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK.
Biochem Biophys Res Commun. 2014 Apr 25;447(1):128-32. doi: 10.1016/j.bbrc.2014.03.117. Epub 2014 Apr 1.
The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulates multiple antioxidants, Phase II detoxification enzymes and other cytoprotective enzymes in cells. Activation of Nrf2 is recognised as being of potential therapeutic benefit in inflammatory-diseases whereas more recently, it has become clear that the inhibition of Nrf2 may have benefit in the alleviation of resistance in some tumour types. A potential G-quadruplex forming sequence was identified in the promoter region of Nrf2, close to a number of putative transcription factor binding sites. Characterisation of the sequence 5'-d[GGGAAGGGAGCAAGGGCGGGAGGG]-3' using CD spectroscopy, imino proton NMR resonances and UV melting experiments demonstrated the formation of a parallel intramolecular G-quadruplex in the presence of K(+) ions. Incubation with 9-aminoacridine ligands induced a switch from antiparallel to parallel forms. The presence of a G-quadruplex forming sequence in the promoter region of Nrf2 suggests an approach to targeting the production of the protein through stabilisation of the structure, thereby avoiding resistance to antitumour drugs.
转录因子核因子（红系衍生2）样2（Nrf2）可调节细胞中的多种抗氧化剂、Ⅱ相解毒酶及其他细胞保护酶。Nrf2的激活被认为在炎症性疾病中具有潜在治疗益处，而最近已明确，抑制Nrf2可能有益于缓解某些肿瘤类型的耐药性。在Nrf2启动子区域靠近多个假定转录因子结合位点处鉴定出一个潜在的G-四链体形成序列。利用圆二色光谱、亚氨基质子核磁共振共振及紫外熔解实验对序列5'-d[GGGAAGGGAGCAAGGGCGGGAGGG]-3'进行表征，结果表明在K(+)离子存在下形成了平行分子内G-四链体。与9-氨基吖啶配体孵育可诱导从反平行形式转变为平行形式。Nrf2启动子区域存在G-四链体形成序列提示了一种通过稳定该结构来靶向蛋白质产生的方法，从而避免肿瘤对抗肿瘤药物产生耐药性。
