Cadmium Induces Conformational Modifications of Wild-type p53 and Suppresses p53 Response to DNA Damage in Cultured Cells

Méplan, Catherine; Mann, Kristine; Hainaut, Pierre

doi:10.1074/jbc.274.44.31663

Cited by 181 publications

(114 citation statements)

References 55 publications

(59 reference statements)

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“…p53 initiates apoptosis during high levels of stress (Schwartz and Rotter, 1998), and MT has been shown to play a role in different aspects of apoptosis. Further evidence is provided by a recent study showing that cadmium can affect the stability and DNAbinding activity of p53 (Méplan et al, 1999). In MCF7 cells, 10 mM of CdCl 2 caused an increase in p53 protein level and DNA binding activity.…”

Section: Discussionmentioning

confidence: 93%

“…In addition, MT may have antioxidant properties because of its high cysteine content which may protect against DNA damage (Cai et al, 1996). A recent study has shown that treatment of MCF7 cells with 10 mM CdCl 2 can increase MT-IIA isoform and can protect against cadmium toxicity (Méplan et al, 1999). Since MCF7 cells were much more sensitive to cadmium toxicity as compared to HCC1806 and MDA-MB-231, a higher induction of MT in MCF7 cells may be required to protect against cytotoxicity and DNA damage.…”

Section: Discussionmentioning

confidence: 99%

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Potential role of p53 on metallothionein induction in human epithelial breast cancer cells

Fan

Cherian

2002

Br J Cancer

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The expression and induction of metallothionein has been associated with protection against oxidative stress and apoptosis. This study examines the effect of tumour suppressor protein p53 on metallothionein expression following CdCl 2 treatment in eight human epithelial breast cancer cell lines differing in p53 and oestrogen-receptor status. Cells were treated with 10 mM CdCl 2 for 24 h and metallothionein protein levels were measured by cadmium binding assay. MCF7 cells which are p53-positive (p53+) and oestrogen-receptor-positive showed a large induction in metallothionein synthesis by 10.79+1.36-fold. Other breast cancer cell lines which are p53-negative (p537) and oestrogen-receptor-negative or weakly oestrogenreceptor-positive showed a small induction ranging from 1.40+0.10 to 3.65+0.30-fold. RT -PCR analysis showed an induction of metallothionein mRNA in MCF7 cells by about 1.61+0.08-fold, while in HCC1806 cells (p537, oestrogenreceptor-negative) by 1.11+0.13-fold, and in MDA-MB-231 (p537, oestrogen-receptor-negative) by 1.25+0.06-fold. Metallothionein localisation was determined by immunohistochemical staining. Prior to metal treatment, metallothionein was localised mainly in the cytoplasm of MCF7 and MDA-MB-231 cells. After treatment with 10 mM CdCl 2 for 24 h, MCF7 cells showed intense nuclear and cytoplasmic staining for metallothionein, while MDA-MB-231 cells showed staining in the cytoplasm with weak nuclear staining. Apoptosis induced by 10 -40 mM CdCl 2 at time points between 4 and 48 h was examined with TUNEL assay. In MCF7 cells, apoptosis increased with higher concentrations of CdCl 2 , it peaked at 6 -8 h and appeared again at 48 h for all concentrations of CdCl 2 tested. In MDA-MB-231 cells, apoptosis remained at low levels for 10 -40 mM CdCl 2 at all time points. Studies on cadmium uptake showed similar uptake and accumulation of cadmium at 8 and 24 h in all the cell lines. The data demonstrate that treatment of epithelial breast cancer cells with 10 mM CdCl 2 for 24 h caused a greater induction of metallothionein protein and mRNA expression in p53+ and oestrogen-receptor-positive cells as compared to p537 and oestrogen-receptor-negative or weakly oestrogen-receptor-positive cells. This effect may be associated with the occurrence of apoptosis and suggests a role for p53 and oestrogen-receptor on the expression and induction of metallothionein in epithelial cells.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Potential role of p53 on metallothionein induction in human epithelial breast cancer cells

Fan

Cherian

2002

Br J Cancer

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“…In this respect, it is known that p53 has a metal-binding feature and is inactivated by exposure to cadmium ions. 24,33 Accordingly, we propose that the metal-binding site in p53 may be targeted by the vanadate anion(s).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, to pursue other possibilities, we examined the effects of vanadate on the conformation of p53 using the anti-p53 PAb 240 mAb as a probe for the inactivated form of p53. [22][23][24] In nondenaturing conditions, PAb 240 mAb recognizes the inactivated form of p53 but not the normal form, whereas the DO-1 mAb recognizes both forms. PAb 240 mAb immunoprecipitated the p53 from irradiated MOLT-4 cells treated with vanadate but not from cells exposed to X-rays alone ( Figure 8a).…”

Section: Vanadate Suppresses P53-dependent Dna Damage-induced Apoptosismentioning

confidence: 99%

Sodium orthovanadate suppresses DNA damage-induced caspase activation and apoptosis by inactivating p53

et al. 2005

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We previously reported that p42/SETb is a substrate for caspase-7 in irradiated MOLT-4 cells, and that treating the cells with sodium orthovanadate (vanadate) inhibits p42/SETb's caspase-mediated cleavage. Here, we initially found that the inhibitory effect of vanadate was due to the suppression of caspase activation but not of caspase activity. Further investigations revealed that vanadate suppressed upstream of apoptotic events, such as the loss of mitochondrial membrane potential, the conformational change of Bax, and p53 transactivation, although the accumulation, total phosphorylation, and phosphorylation of six individual sites of p53 were not affected. Importantly, vanadate suppressed p53-dependent apoptosis, but not p53-independent apoptosis. Finally, gel-shift and chromatin immunoprecipitation assays conclusively demonstrated that vanadate inhibits the DNA-binding activity of p53. Vanadate is conventionally used as an inhibitor of protein tyrosine phosphatases (PTPs); however, we recommend that the influence of vanadate not only on PTPs but also on p53 be considered before using it.

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“…Experimental studies suggest several pathways to explain association of Cd with human breast cancer [8,10,11]. There is evidence that Cd may have estrogenicity [8,12,13].…”

Section: Introductionmentioning

confidence: 99%

Cadmium concentration in biological media of breast cancer patients

Strumylaitė

Boguševičius

Abdrachmanovas

et al. 2010

Breast Cancer Res Treat

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The study aimed to determine and compare cadmium (Cd) concentration in different biological media of breast cancer and benign breast tumor patients. Methods Concentration of Cd was determined in breast tissue, urine and blood of 57 breast cancer and 51 benign tumor patients. Two samples of breast tissue from each patient, i.e. tumor and healthy tissue were taken for the analysis. Cd in biological media was determined by atomic absorption spectrometry (Perkin-Elmer, Zeeman 3030). Results The mean Cd concentration in breast cancer patients was 0.053 µg/g (95% CI=0.042-0.065) for tumor sample and 0.02 µg/g (95% CI=0.014-0.026) for healthy breast tissue sample (p<0.001). In benign tumor patients the figures were following: 0.037 µg/g (95% CI=0.023-0.051) and 0.032 µg/g (95% CI=0.018-0.047) (p>0.05). Cd content in malignant tumor significantly differed from that in benign tumor (p<0.01). Cancer patients with positive estrogenreceptors had significantly greater concentration of breast tissue Cd compared to patients with negative estrogenreceptors (p=0.035). Adjusted for creatinine Cd in urine was significantly higher in cancer patients than in controls (p<0.001). In cancer patients a positive Spearman's correlation was found between Cd in tumor and healthy breast tissue, blood (r=0.44 and r=0.39, respectively, p<0.01). Correlation between Cd in urine of cancer patients and number of cigarettes smoked during lifetime was suggestive (r=0.59, p=0.075). Conclusion The data obtained show higher concentration of cadmium in breast tumor and urine of cancer patients and support a possible relationship between cadmium and breast cancer.

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Cadmium Induces Conformational Modifications of Wild-type p53 and Suppresses p53 Response to DNA Damage in Cultured Cells

Cited by 181 publications

References 55 publications

Potential role of p53 on metallothionein induction in human epithelial breast cancer cells

Potential role of p53 on metallothionein induction in human epithelial breast cancer cells

Sodium orthovanadate suppresses DNA damage-induced caspase activation and apoptosis by inactivating p53

Cadmium concentration in biological media of breast cancer patients

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