REPRESSION OF PROTEIN-KINASE-C AND STIMULATION OF CYCLIC-AMP RESPONSEELEMENTS BY FUMONISIN, A FUNGAL ENCODED TOXIN WHICH IS A CARCINOGEN

Fusarium moniliforme (FM) is a major fungal pathogen of corn and is in volved with stalk rot disease. FM is widely spread throughout the worl d, including the United States. Most strains of FM produce several myc otoxins, the most prominent of which is called fulmination. Recent epi demiological studies indicated that ingestion of fumonisin correlates with a higher incidence of esophageal cancer in Southern and Northern Africa and China. Furthermore, fumonisin causes a neurodegenerative di sease in horses, induces hepatic cancer in rats, and induces pulmonary edema in swine. Considering that high levels of fumonisin have been d etected in healthy and diseased corn grown in the United States, fumon isin may pose a health threat to humans and livestock animals. Structu rally, fumonisin resembles sphingolipids which are present in the memb ranes of animal and plant cells. At the present time, very little is k nown concerning the mechanism by which fumonisin elicits its carcinoge nic effect. Our studies indicate that fumonisin represses expression o f protein kinase C and AP-1-dependent transcription. In contrast, fumo nisin stimulated a simple promoter containing a single cyclic AMP resp onse element. Since fumonisin did not alter protein kinase A activity, it appears that cyclic AMP response element activation was independen t of protein kinase A. It is hypothesized that the ability of fumonisi n to alter signal transduction pathways plays a role in carcinogenesis .