Yang Hyun, Chung Duk Hwa, Kim Yung Bu, Choi Yung Hyun, Moon Yuseok
Department of Microbiology and Immunology and Medical Research Institute, Pusan National University School of Medicine, Busan 602-739, Republic of Korea.
Toxicology. 2008 Jan 14;243(1-2):145-54. doi: 10.1016/j.tox.2007.10.002. Epub 2007 Oct 7.
Deoxynivalenol (DON) and other trichothecene mycotoxins mediate a broad range of epithelial injury including atrophic growth inhibition and inflammation in the human gastrointestinal and respiratory tracts. The purpose of this study was to test the hypothesis that DON alters the cell cycle progress linked to the pathogenesis in the human epithelium. We demonstrated that human epithelial cells underwent G(2)/M phase arrest in response to DON treatment without significant increase in apoptotic cell death. Moreover, cells deficient in p21 or p53 gene expression showed the attenuated response of G(2)/M phase arrest by DON. Gene expression of p21 was also induced by DON treatment in a dose-dependent manner with no increase in p53 protein levels, suggesting p53-independent p21 induction. Signaling pathways associated with DON-induced p21 gene expression included PI3 kinase and ERK1/2 MAP kinase cascade. Particularly, ERK1/2 signal was associated with DON-induced p21 mRNA stabilization in the human epithelial cells. Taken together, deoxynivalenol arrested epithelial cell cycle at G(2)/M phase via elevated p21 gene expression.
脱氧雪腐镰刀菌烯醇（DON）和其他单端孢霉烯族霉菌毒素可介导多种上皮损伤，包括人类胃肠道和呼吸道的萎缩性生长抑制及炎症。本研究的目的是验证DON改变与人类上皮细胞发病机制相关的细胞周期进程这一假说。我们证明，人类上皮细胞在DON处理后会发生G(2)/M期阻滞，且凋亡细胞死亡无显著增加。此外，p21或p53基因表达缺陷的细胞对DON诱导的G(2)/M期阻滞反应减弱。DON处理还以剂量依赖方式诱导p21基因表达，而p53蛋白水平无增加，提示p21的诱导不依赖p53。与DON诱导p21基因表达相关的信号通路包括PI3激酶和ERK1/2丝裂原活化蛋白激酶级联反应。特别是，ERK1/2信号与人类上皮细胞中DON诱导的p21 mRNA稳定性相关。综上所述，脱氧雪腐镰刀菌烯醇通过升高p21基因表达使上皮细胞周期阻滞在G(2)/M期。
