title: Microcystin-LR stabilizes c-myc protein by inhibiting protein phosphatase 2A in HEK293 cells.
abstract: 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.
authors.affiliation: College of Fisheries, Huazhong Agricultural University, Wuhan, China; Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology of China, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Fan
authors.affiliation: Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology of China, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; School of Petrochemical Engineer, Changzhou University, Changzhou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology of China, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China. Electronic address: xieping@ihb.ac.cn.
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.affiliation: Key Laboratory of Biodiversity and Conservation of Aquatic Organisms, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China. Electronic address: w-xiao@ihb.ac.cn.
authors.forename: Wuhan
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology of China, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Key Laboratory of Biodiversity and Conservation of Aquatic Organisms, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Ji
authors.affiliation: Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology of China, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Sujuan
authors.initials: S
authors.lastname: Zhao
mesh_terms: D001427:Bacterial Toxins / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008387:Marine Toxins; D052998:Microcystins / Q000494:pharmacology*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors*; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; C000715470:MAS1 protein, human; D008387:Marine Toxins; D052998:Microcystins; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D054648:Protein Phosphatase 2; C057862:cyanoginosin LR
keywords: Carcinogenicity; Microcystin-LR; Protein phosphatase 2A; c-myc