Microcystin-LR is the most toxic and the most frequently encountered toxin produced by the cyanobacteria in the contaminated aquatic environment. Previous studies have demonstrated that
Microcystin-LR is a potential
carcinogen for animals and humans, and the International Agency for Research on
Cancer has classified
Microcystin-LR as a possible human
carcinogen. However, the precise molecular mechanisms of
Microcystin-LR-induced
carcinogenesis remain a mystery. C-myc is a proto-oncogene, abnormal expression of which contributes to the
tumor development. Although several studies have demonstrated that
Microcystin-LR could induce c-myc expression at the transcriptional level, the exact connection between
Microcystin-LR toxicity and c-myc response remains unclear. In this study, we showed that the c-myc
protein increased in HEK293 cells after exposure to
Microcystin-LR. Coexpression of
protein phosphatase 2A and two stable c-myc
protein point mutants (either c-myc(T58A) or c-myc(S62A)) showed that
Microcystin-LR increased c-myc
protein level mainly through inhibiting
protein phosphatase 2A activity which altered the phosphorylation status of
serine 62 on c-myc. In addition, we also showed that
Microcystin-LR could increase c-myc promoter activity as revealed by
luciferase reporter assay. And the TATA box for P1 promoter of c-myc might be involved. Our results suggested that
Microcystin-LR can stimulate c-myc transcription and stabilize c-myc
protein, which might contribute to hepatic
tumorigenesis in animals and humans.