Characterization of cell-cycle arrest by fumonisin B1 in CV-1 cells.

Abstract

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.

• Authors: J R Ciacci-Zanella, A H Merrill Jr, E Wang, C Jones
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) 1998 Sep-Oct Vol. 36 Issue 9-10 Pg. 791-804 ISSN: 0278-6915 [Print] England
• PMID: 9737426 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carboxylic Acids
• Carcinogens, Environmental
• Cyclin E
• Enzyme Inhibitors
• Fumonisins
• Retinoblastoma Protein
• Tumor Suppressor Protein p53
• fumonisin B1
• Protein Serine-Threonine Kinases
• CDC2-CDC28 Kinases
• Cyclin-Dependent Kinase 2
• Cyclin-Dependent Kinases
• Sphingosine
• safingol

Topics

• Animals
• Blotting, Western
• CDC2-CDC28 Kinases
• COS Cells
• Carboxylic Acids (toxicity)
• Carcinogens, Environmental (toxicity)
• Cell Cycle (drug effects)
• Cell Line
• Chlorocebus aethiops
• Cyclin E (analysis)
• Cyclin-Dependent Kinase 2
• Cyclin-Dependent Kinases (analysis, antagonists & inhibitors)
• Enzyme Inhibitors (toxicity)
• Fumonisins
• Protein Serine-Threonine Kinases (analysis, antagonists & inhibitors)
• Retinoblastoma Protein (analysis)
• Sphingosine (analogs & derivatives, analysis)
• Tumor Suppressor Protein p53 (analysis)