RGD Reference Report - Cadmium toxicity is caused by accumulation of p53 through the down-regulation of Ube2d family genes in vitro and in vivo. - Rat Genome Database

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Cadmium toxicity is caused by accumulation of p53 through the down-regulation of Ube2d family genes in vitro and in vivo.

Authors: Tokumoto, Maki  Fujiwara, Yasuyuki  Shimada, Akinori  Hasegawa, Tatsuya  Seko, Yoshiyuki  Nagase, Hisamitsu  Satoh, Masahiko 
Citation: Tokumoto M, etal., J Toxicol Sci. 2011 Apr;36(2):191-200.
RGD ID: 13830870
Pubmed: PMID:21467746   (View Abstract at PubMed)

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.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Ube2d2bRatcellular response to cadmium ion  IEP  RGD 
Ube2d3Ratcellular response to cadmium ion  IEP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ube2d2b  (ubiquitin-conjugating enzyme E2D 2B)
Ube2d3  (ubiquitin-conjugating enzyme E2D 3)


Additional Information