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Evidence that a wortmannin-sensitive signal transduction pathway regulates aflatoxin biosynthesis

     Department of Pharmacology, Institute of Biomedical Science, Hanyang University, Seoul, South Korea

Ludmila V. Roze

     Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan

John E. Linz ¹

     Department of Food Science and Human Nutrition, Department of Microbiology and Molecular Genetics, National Food Safety and Toxicology Center, 234B GM Trout Building, Michigan State University, East Lansing, Michigan 48823

A signal transduction pathway involving cAMP and protein kinase A (PKA) regulates aflatoxin accumulation and nor-1 and ver-1 (aflatoxin structural genes) promoter function in Aspergillus parasiticus by modulating expression of a key transcriptional activator, AflR. To understand the function of this pathway in greater detail we treated A. parasiticus in culture with wortmannin, a frequently used probe of phosphatidyl inositol (PI)-3 kinase activity. A. parasiticus D8D3 (nor-1::GUS reporter) and I4 (ver- ::GUS reporter) were grown on a defined solid growth medium (GMS agar) under aflatoxin-inducing conditions. GMS containing wortmannin (1 µM) reduced aflatoxin B₁ accumulation up to 15-fold accompanied by a similarly large decrease in ver-1 and nor-1 promoter activity. Wortmannin inhibited growth (colony diameter) and asexual sporulation but to a much smaller extent. Wortmannin treatment increased intracellular cAMP levels up to 25-fold; total PKA activity also increased within 10 min of wortmannin exposure. These data support a regulatory model in which PI-3 kinase activity modulates intracellular cAMP accumulation and PKA activity. This in turn regulates AflR expression and activity, aflatoxin gene expression and aflatoxin accumulation.

Key words: aflatoxin, Aspergillus parasiticus, phosphatidyl inositol (PI) 3-Kinase, phosphodiesterase, signal transduction, wortmannin