Xie T X, Misumi J, Aoki K, Zhao W Y, Liu S Y
Department of Public Health and Hygiene, Oita Medical University, Hasama, Oita 879-5593, Japan.
Int J Oncol. 2000 Oct;17(4):737-42. doi: 10.3892/ijo.17.4.737.
P53 plays a critical role in G1 checkpoint after DNA damage. MDM2 gene is a p53 target gene and its protein forms a feedback loop with p53 and inhibits p53-mediated G1 arrest. Sterigmatocystin (ST) is a mycotoxin and carcinogen. In this study we show that exposure of cells to ST for 12 or 24 h resulted in failure of G1 arrest at both time points. Accordingly, p53 protein was not increased and p21WAF1 expression was inhibited at 12 h, and both proteins were weakly induced at 24 h after treatment with ST. Meanwhile, MDM2 protein was induced in a p53-dependent fashion by ST at both 12 and 24 h. The induction of MDM2 was coincident with the cellular responses of p53 and p21WAF1, and might contribute to the failure of G1 arrest in ST-treated cells. In addition, ST-treated cells exhibited G2M arrest, regardless of p53 status. Our results indicate that the carcinogenic effects of ST seem to be mediated by failure of p53-mediated G1 checkpoint.
P53在DNA损伤后的G1期检查点中起关键作用。MDM2基因是一个p53靶基因，其蛋白与p53形成一个反馈环，并抑制p53介导的G1期阻滞。柄曲霉素（ST）是一种霉菌毒素和致癌物。在本研究中，我们发现细胞暴露于ST 12小时或24小时后，在这两个时间点均导致G1期阻滞失败。相应地，在处理ST 12小时时，p53蛋白未增加且p21WAF1表达受到抑制，而在处理ST 24小时后，这两种蛋白均受到微弱诱导。同时，在12小时和24小时时，ST均以p53依赖的方式诱导MDM2蛋白表达。MDM2的诱导与p53和p21WAF1的细胞反应一致，并且可能导致ST处理的细胞中G1期阻滞失败。此外，无论p53状态如何，ST处理的细胞均表现出G2M期阻滞。我们的结果表明，ST的致癌作用似乎是由p53介导的G1期检查点失败所介导的。
