Cadmium induces cell cycle arrest in rat kidney epithelial cells in G2/M phase.
Cadmium (Cd) has been reported to cause cell cycle arrest in various cell types by p53-dependent and -independent mechanisms. This study was designed to investigate cell cycle progression in kidney cells that are the target of chronic Cd toxicity. Rat renal proximal tubular epithelial cells, NRK-52E, were treated with up to 20 microM CdCl2 in DMEM containing 10% calf serum for up to 24 h. Flow cytometric analysis revealed time- and concentration-dependent increases in cells in G2/M phase of the cell cycle. As compared to the control cells, the cells exposed to 20 microM Cd showed a doubling of the number of cells in this phase after 24 h. The cell cycle arrest was associated with a decrease in protein levels of both cyclins A and B. Further investigation into the mechanism revealed that Cd treatment led to down-modulation of cyclin-dependent kinases, Cdk1 and Cdk2, apparently by elevating the expression of cyclin kinase inhibitors, KIP1/p27 and WAF1/p21. Furthermore, the wild-type p53 DNA-binding activity was up-regulated. Based on these observations, it appears that Cd causes G2/M phase arrest in NRK-52E cells via elevation of p53 activity, increasing the expression of cyclin kinase inhibitors p27 and p21, and decreasing the expression of cyclin-dependent kinases Cdk1 and 2, and of cyclins A and B.
Xie
Jianxun
J
Department of Biomedical and Pharmaceutical Sciences and Center for Molecular Toxicology, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA.
Shaikh
Zahir A
ZA
D000818:Animals; D002104:Cadmium / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016213:Cyclins / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects*; D007668:Kidney / Q000166:cytology* / Q000187:drug effects; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016213:Cyclins; D004791:Enzyme Inhibitors; D016159:Tumor Suppressor Protein p53; D002104:Cadmium; D018844:Cyclin-Dependent Kinases