4.7 Article

Copper exposure induces hepatic G0/G1 cell-cycle arrest through suppressing the Ras/PI3K/Akt signaling pathway in mice

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出版社

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ecoenv.2021.112518

关键词

Copper; G0; G1 cell-cycle arrest; Ras; PI3K; Akt signaling pathway; Liver

资金

  1. Program for Changjiang Scholars and the University Innovative Research Team [IRT 0848]
  2. Shuangzhi Project of Sichuan Agricultural University [03572437, 03573050, 1921993267]

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The study demonstrates that high copper exposure leads to hepatocellular G0/G1 cell-cycle arrest in mice by suppressing the Ras/PI3K/Akt signaling pathway and reducing the levels of CDK2/4 and cyclin E/D, essential for the G1-S transition.
Copper (Cu), as a common chemical contaminant in environment, is known to be toxic at high concentrations. The current research demonstrates the effects of copper upon hepatocyte cell-cycle progression (CCP) in mice. Institute of cancer research (ICR) mice (n = 240) at an age of four weeks were divided randomly into groups treated with different doses of Cu (0, 4, 8, and 16 mg/kg) for 21 and 42 days. Results showed that high Cu exposure caused hepatocellular G0/G1 cell-cycle arrest (CCA) and reduced cell proportion in the G2/M phase. G0/G1 CCA occurred with down-regulation (p < 0.05) of Ras, p-PI3K (Tyr458), p-Akt (Thr308), p-forkhead box O3 (FOXO3A) (Ser253), p-glycogen synthase kinase 3-beta (GSK3-beta) (Ser9), murine double minute 2 (MDM2) protein, and mRNA expression levels, and up-regulation (p < 0.05) of PTEN, p-p53 (Ser15), p27, p21 protein, and mRNA expression levels, which subsequently suppressed (p < 0.05) the protein and mRNA expression levels of CDK2/4 and cyclin E/D. These results indicate that Cu exposure suppresses the Ras/PI3K/Akt signaling pathway to reduce the level of CDK2/4 and cyclin E/D, which are essential for the G1-S transition, and finally causes hepatocytes G0/G1 CCA.

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