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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.
AuthorsHuihui Fan, Yan Cai, Ping Xie, Wuhan Xiao, Jun Chen, Wei Ji, Sujuan Zhao
JournalToxicology (Toxicology) Vol. 319 Pg. 69-74 (May 07 2014) ISSN: 1879-3185 [Electronic] Ireland
PMID24607848 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Chemical References
  • Bacterial Toxins
  • MAS1 protein, human
  • Marine Toxins
  • Microcystins
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • Protein Phosphatase 2
  • cyanoginosin LR
Topics
  • Bacterial Toxins (pharmacology)
  • HEK293 Cells
  • Humans
  • Marine Toxins
  • Microcystins (pharmacology)
  • Protein Phosphatase 2 (antagonists & inhibitors)
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-myc (genetics, metabolism)
  • RNA, Messenger (metabolism)

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