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

Tokumoto, Maki; Fujiwara, Yasuyuki; Shimada, Akinori; Hasegawa, Tatsuya; Seko, Yoshiyuki; Nagase, Hisamitsu; Satoh, Masahiko

doi:10.2131/jts.36.191

Cited by 79 publications

(88 citation statements)

References 24 publications

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“…Recently, several studies have suggested that Cd toxicity is associated with perturbation of the ubiquitin (Ub) proteasome system (Figueiredo-Pereira et al, 2002;Yu et al, 2008Yu et al, , 2011Tokumoto et al, 2011). Our previous study has demonstrated that Cd decreases expression of Ub proteasome system (UPS)-related genes in rat proximal tubular cells and mouse kidney (Tokumoto et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Involvement of ubiquitin-coding genes in cadmium-induced protein ubiquitination in human proximal tubular cells

et al. 2015

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-Cadmium (Cd) is a toxic heavy metal with a long half-life in humans. It causes disorders of various tissue systems, including the kidney, and is associated with protein aggregation. Our previous study demonstrated Cd-induced suppression of the UBE2D gene family, one of the ubiquitin-conjugating enzyme families. However, the precise role of ubiquitin-coding genes in Cd toxicity remains to be understood. In this study, we investigated the effect of Cd on expression of the ubiquitin-coding genes UBB, UBC, UBA80, and UBA52 in HK-2 human proximal tubular cells. Prior to the appearance of Cd toxicity, the UBB, UBC, and UBA80 expression levels increased following Cd treatment. Knockdown of UBB by siRNA transfection significantly decreased Cd cytotoxicity. Notably, Cd induces ubiquitinated protein levels in HK-2 cells, and knockdown of UBB blocked this process. These results suggest that UBB is involved in Cd-induced increase of protein ubiquitination, and that accumulation of ubiquitinated proteins through increased UBB expression may contribute to Cd toxicity in HK-2 cells.

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Section: Introductionmentioning

confidence: 99%

“…Our previous study has demonstrated that Cd decreases expression of Ub proteasome system (UPS)-related genes in rat proximal tubular cells and mouse kidney (Tokumoto et al, 2011). In addition to Cd, inorganic arsenic and inorganic mercury decrease gene expression of UPS-related proteins, such as Ube2d1, Ube2d2, and Ube2d4 .…”

Section: Introductionmentioning

confidence: 99%

Involvement of ubiquitin-coding genes in cadmium-induced protein ubiquitination in human proximal tubular cells

et al. 2015

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“…Although many researchers have studied the mechanism of Cd toxicity using various cultured cells, the underlying mechanism of Cd toxicity remains unclear. Recent studies have shown that changes in the gene expression may be involved in Cd toxicity in several cell types (Tokumoto et al, 2011a;Fujiwara et al, 2012). DNA microarray analysis provides beneficial information for understanding gene changes following exposure to toxic metals (Tokumoto et al, 2011b;Hwang et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Gene expression analysis using DNA microarray in HK-2 human proximal tubular cells treated with cadmium

et al. 2013

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-We examined the alteration of gene expression in HK-2 human proximal tubular cells exposed to cadmium (Cd) using DNA microarray analysis. Cd increased the expression of 30 genes, including 7 genes coding for heat shock proteins, more than 2.0-fold and decreased the expression of 21 genes, including transcription-related genes, such as AP2B1, HOXA7, HOXA9 and TCEB2, less than 0.5-fold prior to the appearance of cytotoxicity in HK-2 cells.

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“…2). Several previous studies showed that Cd disturbed UPS in several cell lines (Tokumoto et al, 2011;Yu et al, 2011;Du et al, 2014;Lee et al, 2016). Therefore, we investigated whether gestational Cd exposure disrupted whole UPS in the fetal liver.…”

Section: Resultsmentioning

confidence: 96%

“…Previous studies showed that Cd disturbed the ubiquitin-proteasome system (UPS) in several cell lines (Tokumoto et al, 2011;Yu et al, 2011;Du et al, 2014;Lee et al, 2016). Furthermore, Cd changes the activities of transcription factors involved in the transcription of UPS-related genes (Tokumoto et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Effect of gestational cadmium exposure on fetal growth, polyubiquitinated protein and monoubiqutin levels in the fetal liver of mice

et al. 2018

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-Cadmium (Cd) is an environmental pollutant present in contaminated water, food and soil. Cd adversely affects fetal development. We exposed pregnant mice to daily oral doses of 5 and 10 mg/kg Cd and examined fetal growth. It was demonstrated that the exposure to Cd (10 mg/kg) during gestation caused fetal growth retardation (FGR). Investigation of the ubiquitin-proteasome system in fetal livers of mice exposed to gestational Cd revealed increased polyubiquitinated protein accumulation, contrasting with decreased levels of monoubiquitin protein. Moreover, the expression level of Ubc (encoding polyubiquitin C protein) was significantly decreased in 5 and 10 mg/kg Cd-treated groups in comparison with the control group. Therefore, we propose that decrease of monoubiquitin level and accumulation of polyubiquitinated protein in the fetal liver may be important factors in Cd-induced FGR.

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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

Cited by 79 publications

References 24 publications

Involvement of ubiquitin-coding genes in cadmium-induced protein ubiquitination in human proximal tubular cells

Involvement of ubiquitin-coding genes in cadmium-induced protein ubiquitination in human proximal tubular cells

Gene expression analysis using DNA microarray in HK-2 human proximal tubular cells treated with cadmium

Effect of gestational cadmium exposure on fetal growth, polyubiquitinated protein and monoubiqutin levels in the fetal liver of mice

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