title: Fumonisin B1 induces protein kinase C translocation via direct interaction with diacylglycerol binding site.
abstract: Fumonisins are carcinogenic to rats and are suspected human carcinogens. However, the mechanism(s) of carcinogenesis of fumonisn B1 (FB1) is poorly understood. Multiple signal transduction pathways such as protein kinase C (PKC) have been shown to play an important role in carcinogenesis. This study was undertaken to evaluate whether FB1 affects PKC activation. Similar to tumor-promoting phorbol ester, phorbol 12-myristate-13-acetate (PMA), PKC is also catalytically activated by FB1. Protein kinase C activity and its redistribution in response to FB1 were determined in rat cerebrocortical slices. Cytosolic and membranous PKC activities were determined by histone phosphorylation in the presence of [gamma-32P]ATP, phosphatidyl-L-serine, PMA, and Ca2+. Distribution of gamma PKC isozyme in the presence of FB1 was also assessed by immunoblotting using affinity purified anti-peptide antibodies. Similar to PMA, FB1 added in vitro to rat cerebrocortical slices facilitated PKC translocation from cytosol to membrane in a concentration-dependent manner. This FB1-induced PKC translocation was inhibited by incubation with the inactive 4 alpha-phorbol 12,13-didecanoate. The effects of FB1 and PMA were neither additive nor synergistic. In addition, PMA and FB1-induced PKC enzyme redistribution were inhibited by pretreating tissues with sphingosine. A concentration-related FB1 attenuation of specific phorbol dibutyrate, [3H]PDBu, binding was also observed when cortical membranes were incubated with either PMA or sphingosine. This is the first report of FB1-induced PKC translocation via a direct action on the diacylglycerol site that also binds phorbol esters. Because phorbol esters are well known tumor promoters, we provide a plausible cellular mechanism to explain the carcinogenicity of FB1.
authors.affiliation: Food Research Division, Food Directorate, Health Protection Branch, Health Canada, Sir Frederick Banting Research Centre, Ottawa, Ontario, Canada.
authors.forename: J M
authors.initials: JM
authors.lastname: Yeung
authors.forename: H Y
authors.initials: HY
authors.lastname: Wang
authors.forename: D B
authors.initials: DB
authors.lastname: Prelusky
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002274:Carcinogens, Environmental / Q000633:toxicity*; D046508:Culture Techniques; D004075:Diglycerides / Q000378:metabolism; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D037341:Fumonisins; D007527:Isoenzymes; D008297:Male; D009183:Mycotoxins / Q000633:toxicity*; D010703:Phorbol Esters / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013110:Sphingosine / Q000494:pharmacology
chemical_list: D002274:Carcinogens, Environmental; D004075:Diglycerides; D037341:Fumonisins; D007527:Isoenzymes; D009183:Mycotoxins; D010703:Phorbol Esters; C056933:fumonisin B1; D011493:Protein Kinase C; D013110:Sphingosine