Cadmium-induced DNA damage triggers G(2)/M arrest via chk1/2 and cdc2 in p53-deficient kidney proximal tubule cells

American Journal of Physiology. Renal Physiology
Ulrich BorkFrank Thévenod

Abstract

Carcinogenesis is a multistep process that is frequently associated with p53 inactivation. The class 1 carcinogen cadmium (Cd(2+)) causes renal cancer and is known to inactivate p53. G(2)/mitosis (M) arrest contributes to stabilization of p53-deficient mutated cells, but its role and regulation in Cd(2+)-exposed p53-deficient renal cells are unknown. In p53-inactivated kidney proximal tubule (PT) cells, comet assay experiments showed that Cd(2+) (50-100 microM) induced DNA damage within 1-6 h. This was associated with peak formation of reactive oxygen species (ROS) at 1-3 h, measured with dihydrorhodamine 123, and G(2)/M cell cycle arrest at 6 h, which were abolished by the antioxidant alpha-tocopherol (100 microM). Cd(2+)-induced G(2)/M arrest was enhanced approximately twofold on release from cell synchronization (double thymidine block or nocodazole) and resulted in approximately twofold increase of apoptosis, indicating that G(2)/M arrest mirrors DNA damage and toxicity. The Chk1/2 kinase inhibitor UCN-01 (0.3 microM), which relieves G(2)/M transition block, abolished Cd(2+)-induced G(2) arrest and increased apoptosis. This was accompanied by prevention of Cd(2+)-induced cyclin-dependent kinase cdc2 phosphorylation at tyros...Continue Reading

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Citations

Aug 29, 2013·Archives of Toxicology·Frank Thévenod, Wing-Kee Lee
Mar 26, 2011·Toxicological Sciences : an Official Journal of the Society of Toxicology·Wing-Kee LeeFrank Thévenod
Sep 29, 2011·Mutation Research·Metka Filipič
Feb 2, 2012·The Journal of Toxicological Sciences·Nobuhiko MiuraTatsuya Hasegawa
Feb 27, 2018·Nature Reviews. Nephrology·Xin XuFan Fan Hou
Jan 26, 2013·Journal of Applied Toxicology : JAT·Katsuya UnnoMasayuki Ikeda
Aug 30, 2020·Applied and Environmental Microbiology·Todsapol TechoChoowong Auesukaree
Aug 29, 2020·The Science of the Total Environment·Yu-Mei HsuehChi-Jung Chung
Jan 6, 2018·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Lei XueJinhua Luo

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