Activation of ERK mitogen-activated protein kinase in human cells by the mycotoxin patulin.
Patulin (PAT), a mycotoxin produced by certain species of Penicillium and Aspergillus, is often detectable in moldy fruits and their derivative products. PAT led to a concentration-dependent and time-dependent increase in phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in human embryonic kidney (HEK293) cells, human peripheral blood mononuclear cells (PBMCs), and Madin-Darby canine kidney (MDCK) cells. Exposure of HEK293 cells to concentrations above 5 microM PAT for 30 min induced ERK1/2 phosphorylation; activation of ERK1/2 was also observed after 24 h incubation with 0.05 microM of PAT. Treatment of human PBMCs for 30 min with 30 microM PAT dramatically increased the phosphorylated ERK1/2 levels. Both MEK1/2 inhibitors, U0126 and PD98059, suppressed ERK1/2 activation in either HEK293 or MDCK cells. In HEK293 cells, U0126-mediated inhibition of PAT-induced ERK1/2 phosphorylation resulted in a significant decrease in levels of DNA damage, expressed as tail moment values, in the single cell gel electrophoresis assay. Conversely, U0126 did not affect cell viability, lactate dehydrogenase release, and the DNA synthesis rate in PAT-treated cultures. Exposure of HEK293 cells for 90 min to 15 microM PAT elevated the levels of early growth response gene-1 (egr-1) mRNA, but not of c-fos, fosB, and junB mRNAs. These results indicate that in human cells, PAT causes a rapid and persistent activation of ERK1/2 and this signaling pathway plays an important role in mediating PAT-induced DNA damage and egr-1 gene expression.
Wu
Ting-Shuan
TS
Department of Life Sciences, Chung Shan Medical University, Taichung, Taiwan.
Yu
Feng-Yih
FY
Su
Ching-Chyuan
CC
Kan
Jia-Chi
JC
Chung
Ching-Ping
CP
Liu
Biing-Hui
BH
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics; D004285:Dogs; D051766:Early Growth Response Protein 1; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009153:Mutagens / Q000633:toxicity*; D009570:Nitriles / Q000494:pharmacology; D010365:Patulin / Q000633:toxicity*; D014157:Transcription Factors / Q000235:genetics
D002070:Butadienes; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D009153:Mutagens; D009570:Nitriles; D014157:Transcription Factors; C113580:U 0126; D004247:DNA; D010365:Patulin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3