title: Microcystin-LR promotes cell proliferation in the mice liver by activating Akt and p38/ERK/JNK cascades.
abstract: Microcystin-LR (MC-LR), a heptapeptide produced by blue-green algae, is shown to induce cytotoxicity by inhibiting protein phosphatase 2A (PP2A) activity. Our previous study revealed that MC-LR promoted cell proliferation in vitro by activating the Akt/mTORC1/S6K1 pathway. This study aims to further investigate the effects of MC-LR on cell proliferation and the correlated mechanisms in vivo. Mice were injected intraperitoneally with 20-80 μg/kg/d MC-LR from 2 h (hours) to 4 d (days). The results showed that the associations of MC-LR with PP2A/C (PP2A C subunit) were concentration-dependent but not time-dependent in the liver, whereas the total PP2A activity was inhibited in both concentration and time dependent manners. The PP2A regulator α4 was found to release its associated PP2A/C as MC-LR bound to PP2A/C. Importantly, 80 μg/kg MC-LR promoted liver cell proliferation beginning at 1 d post exposure, and hyperproliferation also occurred in the 40 μg/kg group at 4 d after exposure. Meanwhile, the Akt/mTORC1/S6K1 and Akt/β-catenin signaling pathways were activated as early as at 2 h post exposure. Furthermore, MC-LR also activated ERK/p38/JNK MAPKs as early as at 2 h post exposure, which was supported by the hyperphosphorylation of their substrates, ATF-2, c-Jun and c-Myc. Interestingly, the total c-Jun and c-Myc levels also increased after MC-LR exposure. These findings indicate that MC-LR can also promote cell proliferation in vivo, and the activation of Akt and MAPK signaling pathways due to PP2A inhibition is proposed to participate in this process.
authors: Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors: Jinghui
authors: J
authors: Liu
authors: Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors: Beilei
authors: B
authors: Wang
authors: Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors: Pu
authors: P
authors: Huang
authors: Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors: Hanying
authors: H
authors: Wang
authors: Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors: Kailun
authors: K
authors: Xu
authors: Zhejiang Center for Disease Control and Prevention, Hangzhou 310051, China.
authors: Xiaofeng
authors: X
authors: Wang
authors: Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou 310058, China. Electronic address: xulihong@zju.edu.cn.
authors: Lihong
authors: L
authors: Xu
authors: Department of Biosystem Engineering, College of Biosystem Engineering and Food Science, Zhejiang University, Hangzhou 310058, China. Electronic address: zlguo@zju.edu.cn.
authors: Zonglou
authors: Z
authors: Guo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008387:Marine Toxins; D051379:Mice; D008813:Mice, Inbred ICR; D052998:Microcystins / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D008387:Marine Toxins; D052998:Microcystins; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D054648:Protein Phosphatase 2; C057862:cyanoginosin LR
keywords: Akt; MAPK; Microcystin-LR; PP2A; Proliferation; α4