Julius-Bernstein-Institute for Physiology, Martin-Luther-University Halle-Wittenberg, 06112 Halle (Saale), Germany.
Cells. 2020 Jan 7;9(1):143. doi: 10.3390/cells9010143.
Environmental food contaminants constitute a threat to human health. For instance, the globally spread mycotoxin Ochratoxin A (OTA) contributes to chronic kidney damage by affecting proximal tubule cells via unknown mechanisms. We applied a top-down approach to identify relevant toxicological mechanisms of OTA using RNA-sequencing followed by in-depth bioinformatics analysis and experimental validation. Differential expression analyses revealed that OTA led to the regulation of gene expression in kidney human cell lines, including for genes enriched in cell cycle-related pathways, and OTA-induced gap 1 and 2 (G1 and G2) cell-cycle arrests were observed. Weighted correlation network analysis highlighted cyclin dependent kinase 2 (CDK2) as a putative key regulator of this effect. CDK2 was downregulated by OTA exposure, and its overexpression partially blocked the OTA-induced G1 but not G2 cell-cycle arrest. We, therefore, propose CDK2 as one of the key regulators of the G1 cell-cycle arrest induced by low nanomolar concentrations of OTA.
环境食品污染物对人类健康构成威胁。例如，全球广泛存在的霉菌毒素赭曲霉毒素 A（OTA）通过未知机制影响近端肾小管细胞，导致慢性肾损伤。我们采用自上而下的方法，使用 RNA 测序结合深入的生物信息学分析和实验验证，来识别 OTA 的相关毒性作用机制。差异表达分析表明，OTA 导致肾人细胞系中基因表达的调节，包括细胞周期相关途径中富集的基因，并且观察到 OTA 诱导的间隙 1 和 2（G1 和 G2）细胞周期停滞。加权相关网络分析突出了细胞周期蛋白依赖性激酶 2（CDK2）作为这种作用的潜在关键调节剂。CDK2 被 OTA 暴露下调，其过表达部分阻断了 OTA 诱导的 G1 期但不是 G2 期细胞周期停滞。因此，我们提出 CDK2 是 OTA 诱导的低纳摩尔浓度 G1 期细胞周期停滞的关键调节因子之一。
