Smirnov Artem, Cappello Angela, Lena Anna Maria, Anemona Lucia, Mauriello Alessandro, Di Daniele Nicola, Annicchiarico-Petruzzelli Margherita, Melino Gerry, Candi Eleonora
Department of Experimental Medicine, TOR, University of Rome "Tor Vergata", Rome 00133, Italy.
Department of Systems Medicine, University of Rome "Tor Vergata", Rome 00133, Italy.
Aging (Albany NY). 2018 Nov 16;10(11):3308-3326. doi: 10.18632/aging.101639.
The transcription factor p53 is a key player in the tumour suppressive DNA damage response and a growing number of target genes involved in these pathways has been identified. p53 has been shown to be implicated in controlling cell motility and its mutant form enhances metastasis by loss of cell directionality, but the p53 role in this context has not yet being investigated. Here, we report that ZNF185, an actin cytoskeleton-associated protein from LIM-family of Zn-finger proteins, is induced following DNA-damage. ChIP-seq analysis, chromatin crosslinking immune-precipitation experiments and luciferase assays demonstrate that is a p53 target gene. Upon genotoxic stress, caused by DNA-damaging drug etoposide and UVB irradiation, ZNF185 expression is up-regulated and in etoposide-treated cells, ZNF185 depletion does not affect cell proliferation and apoptosis, but interferes with actin cytoskeleton remodelling and cell polarization. Bioinformatic analysis of different types of epithelial cancers from both TCGA and GTEx databases showed a significant decrease in mRNA level compared to normal tissues. These findings are confirmed by tissue micro-array IHC staining. Our data highlight the involvement of ZNF185 and cytoskeleton changes in p53-mediated cellular response to genotoxic stress and indicate ZNF185 as potential biomarker for epithelial cancer diagnosis.
转录因子p53是肿瘤抑制性DNA损伤反应中的关键因子，并且已经鉴定出越来越多参与这些途径的靶基因。p53已被证明与控制细胞运动有关，其突变形式通过细胞方向性丧失增强转移，但p53在这种情况下的作用尚未得到研究。在这里，我们报告ZNF185，一种来自锌指蛋白LIM家族的肌动蛋白细胞骨架相关蛋白，在DNA损伤后被诱导。ChIP-seq分析、染色质交联免疫沉淀实验和荧光素酶测定表明， 是一个p53靶基因。在由DNA损伤药物依托泊苷和UVB照射引起的基因毒性应激下，ZNF185表达上调，在依托泊苷处理的细胞中，ZNF185缺失不影响细胞增殖和凋亡，但会干扰肌动蛋白细胞骨架重塑和细胞极化。对来自TCGA和GTEx数据库的不同类型上皮癌的生物信息学分析显示，与正常组织相比， mRNA水平显著降低。这些发现通过组织微阵列免疫组化染色得到证实。我们的数据突出了ZNF185和细胞骨架变化在p53介导的对基因毒性应激的细胞反应中的作用，并表明ZNF185作为上皮癌诊断的潜在生物标志物。
原文中“ is a p53 target gene”和“Bioinformatic analysis of different types of epithelial cancers from both TCGA and GTEx databases showed a significant decrease in mRNA level compared to normal tissues.”两处有缺失信息，已按原文翻译。
