Ciacci-Zanella J R, Merrill A H, Wang E, Jones C
Center for Biotechnology, Department of Veterinary and Biomedical Sciences, University of Nebraska, Lincoln 68583, USA.
Food Chem Toxicol. 1998 Sep-Oct;36(9-10):791-804. doi: 10.1016/s0278-6915(98)00034-9.
Fusarium moniliforme is a widespread fungal pathogen which primarily infects corn, but can also infect rice or wheat. Fusarium moniliforme produce several mycotoxins, the most prominent of which is called fumonisin B1 (FB1). Epidemiological studies have indicated that ingestion of fumonisins correlates with a higher incidence of oesophageal cancer in Africa and China. Fumonisins also cause a neurodegenerative disease in horses, induce hepatic cancer in rats, are nephrotoxic in rats, or cause pulmonary oedema in swine. Structurally, fumonisins resemble sphingolipids and can alter sphingolipid biosynthesis. suggesting that sphingolipid alterations play a role in disease and carcinogenesis. Previous studies determined that FB1 blocked cell-cycle progression in CV-1 cells but not COS-7 cells. Herein, we have examined the effects that FB1 treatment has on cell-cycle regulatory proteins. Our studies established that FB1 treatment of CV-1 cells, but not COS-7 cells, leads to dephosphorylation of the retinoblastoma (Rb) protein. Cyclin dependent kinase 2 (CDK2) activity was repressed five- to 10-fold and cyclin E protein levels were lower in CV-1 cells after fumonisin treatment. Two CDK inhibitors, Kip1 and Kip2, were induced within 3 hours after fumonisin treatment of CV-1 cells, suggesting these two proteins mediate cell-cycle arrest induced by FB1. This mycotoxin caused large increases in sphinganine within 3 hours after addition of FB1. As sphingoid bases are known to induce Rb phosphorylation, this increase in sphinganinie might be the stimulus for the suppression of cyclin dependent kinase activities via Kip1 and Kip2. The ability of FB1 to accumulate sphingosine or sphinganine and arrest the cell cycle in some cells but not others may play an important role in carcinogenesis or disease.
串珠镰刀菌是一种广泛存在的真菌病原体，主要感染玉米，但也可感染水稻或小麦。串珠镰刀菌会产生多种霉菌毒素，其中最主要的是伏马毒素B1（FB1）。流行病学研究表明，在非洲和中国，摄入伏马毒素与食管癌发病率较高相关。伏马毒素还会导致马患神经退行性疾病，诱发大鼠肝癌，对大鼠具有肾毒性，或导致猪肺水肿。从结构上看，伏马毒素类似于鞘脂，能够改变鞘脂生物合成。这表明鞘脂改变在疾病和致癌过程中发挥作用。先前的研究确定，FB1可阻断CV - 1细胞的细胞周期进程，但对COS - 7细胞无此作用。在此，我们研究了FB1处理对细胞周期调节蛋白的影响。我们的研究证实，用FB1处理CV - 1细胞而非COS - 7细胞，会导致视网膜母细胞瘤（Rb）蛋白去磷酸化。伏马毒素处理后，CV - 1细胞中的细胞周期蛋白依赖性激酶2（CDK2）活性被抑制5至10倍，细胞周期蛋白E的蛋白水平降低。在用FB1处理CV - 1细胞3小时内，两种CDK抑制剂KipI和Kip2被诱导产生，这表明这两种蛋白介导了由FB1诱导的细胞周期停滞。添加FB1后3小时内，这种霉菌毒素会使鞘氨醇大量增加。由于鞘氨醇碱基已知可诱导Rb磷酸化，鞘氨醇的这种增加可能是通过Kip1和Kip2抑制细胞周期蛋白依赖性激酶活性的刺激因素。FB1在某些细胞中积累鞘氨醇或鞘氨醇并使细胞周期停滞，而在其他细胞中则不然，这一能力可能在致癌或疾病过程中起重要作用。
