title: Cadmium toxicity is caused by accumulation of p53 through the down-regulation of Ube2d family genes in vitro and in vivo.
abstract: Cadmium (Cd) causes renal dysfunction with damage to kidney proximal tubule cells; however, the precise mechanisms of the toxicity remain unclear. Previously, we found that the expression of Ube2d4 gene, which is a member of the ubiquitin-conjugating enzyme Ube2d family, is suppressed by Cd in NRK-52E rat renal tubular epithelial cells. To investigate the mechanisms of Cd-induced renal toxicity, we examined the effects of Cd on the ubiquitin-proteasome system, particularly the expression and function of Ube2d family members in the NRK-52E cells and mice. Cd markedly decreased the expression of Ube2d1, Ube2d2, Ube2d3 and Ube2d4 prior to the appearance of cytotoxicity in the NRK-52E cells. Cd also dramatically increased p53 protein levels in the cells, without stimulation of p53 gene expression or inhibition of proteasome activity. In addition, Cd induced phosphorylation of p53 and caused apoptosis in the NRK-52E cells. In vivo, we examined the effect of orally administrated Cd for 12 months on the expression of Ube2d genes and accumulation of p53 in the mouse kidney. Chronic Cd exposure also caused suppression of Ube2d genes expression and accumulation of p53. Cd did not induce severe kidney injury, but caused apoptosis in the renal tubules. These results suggest that the Cd-induced accumulation of p53 may be due to inhibition of p53 degradation through the down-regulation of Ube2d family genes, and that Cd induces p53-dependent apoptosis in renal tubular cells. Moreover, Ube2d family members may be one of the critical targets of renal toxicity caused by Cd.
authors.affiliation: Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Tokumoto
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Akinori
authors.initials: A
authors.lastname: Shimada
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Seko
authors.forename: Hisamitsu
authors.initials: H
authors.lastname: Nagase
authors.forename: Masahiko
authors.initials: M
authors.lastname: Satoh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019256:Cadmium Chloride / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics* / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D044763:Ubiquitin-Conjugating Enzymes; D019256:Cadmium Chloride