カドミウムによるUbe2dファミリー遺伝子の発現抑制を介したp53依存的アポトーシス誘導

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Cadmium (Cd), a harmful metal, exerts severe toxic effects on various tissues such as those in the kidney, liver, lung, and bone. In particular, renal toxicity with damage to proximal tubule cells is caused by chronic exposure to Cd. However, the molecular mechanism underlying chronic Cd renal toxicity remains to be understood. In this review, we present our recent findings since we examined to search for the target molecules involved in the renal toxicity of Cd using toxicogenomics. In NRK-52E rat renal tubular epithelial cells, we found using DNA microarrays that Cd suppressed the expression of the gene encoding Ube2d4, a member of the Ube2d family. The Ube2d family consists of selective ubiquitin-conjugating enzymes associated with p53 degradation. Moreover, Cd suppressed the expressions of genes encoding all Ube2d family members (Ube2d1/2/3/4) prior to the appearance of cytotoxicity in NRK-52E cells. Cd markedly increased p53 protein level and induced p53 phosphorylation and apoptosis in the cells. In vivo studies showed that chronic Cd exposure also suppressed Ube2d family gene expression and induced p53 accumulation and apoptosis in the renal tubules of the mouse kidney. These findings suggest that Cd causes p53-dependent apoptosis due to the inhibition of p53 degradation through the down-regulation of Ube2d family genes in NRK-52E cells and mouse kidney. Thus, the Ube2d family genes may be one of the key targets of renal toxicity caused by Cd.