Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China.
Toxicol Lett. 2012 Mar 7;209(2):186-92. doi: 10.1016/j.toxlet.2011.12.011. Epub 2011 Dec 30.
Ochratoxin A (OTA) is a ubiquitous mycotoxin with potential nephrotoxic, hepatotoxic, and immunotoxic effects. Recent work from our laboratory found that OTA evoked G2 phase arrest in GES-1 cells in vitro by modulating the key factors Cdc25C, Cdc2 and cyclinB1, which were critical to the G2/M phase transmission, suggested that OTA-induced G2 arrest mediate at least in part OTA toxicity effect. However, the molecular mechanism of this effect is currently unclear. In the present study, we showed that treatment of GES-1 cells with OTA could induce the activation of MAPK family members ERK and p38. ERK inhibitor PD98059 and p38 inhibitor SB203580 significantly reversed the depression of Cdc25C/p-Cdc25C, Cdc2/p-Cdc2, cyclinB1 as well as the cyclinB1-Cdc2 complex, thereby, abolished the delay in G2 phase. In addition, silencing ERK and p38 expression with siRNA significantly inhibited OTA-induced G2 arrest in GES-1 cells as well. Collectively, these data suggest that the ERK and p38 MAPK signaling pathways play important roles in the regulation of OTA-induced G2 arrest in GES-1 cells.
赭曲霉毒素 A（OTA）是一种普遍存在的真菌毒素，具有潜在的肾毒性、肝毒性和免疫毒性。我们实验室最近的工作发现，OTA 通过调节关键因子 Cdc25C、Cdc2 和 cyclinB1，在体外诱导 GES-1 细胞 G2 期阻滞，这些因子对于 G2/M 期的传递至关重要，这表明 OTA 诱导的 G2 期阻滞至少部分介导了 OTA 的毒性作用。然而，这种效应的分子机制目前尚不清楚。在本研究中，我们表明，OTA 处理 GES-1 细胞可诱导 MAPK 家族成员 ERK 和 p38 的激活。ERK 抑制剂 PD98059 和 p38 抑制剂 SB203580 显著逆转了 Cdc25C/p-Cdc25C、Cdc2/p-Cdc2、cyclinB1 以及 cyclinB1-Cdc2 复合物的抑制，从而使 G2 期阻滞得到恢复。此外，用 siRNA 沉默 ERK 和 p38 的表达也显著抑制了 OTA 诱导的 GES-1 细胞 G2 期阻滞。综上所述，这些数据表明，ERK 和 p38 MAPK 信号通路在调节 OTA 诱导的 GES-1 细胞 G2 期阻滞中发挥重要作用。
