Impact of cadmium, cobalt and nickel on sequence-specific DNA binding of p63 and p73 in vitro and in cells
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
25446071
DOI
10.1016/j.bbrc.2014.11.027
PII: S0006-291X(14)02037-3
Knihovny.cz E-resources
- Keywords
- Cadmium, Cobalt, Heavy metals, Nickel, Sequence-specific DNA binding, p53 protein family,
- MeSH
- Transcriptional Activation MeSH
- Dithiothreitol chemistry MeSH
- DNA-Binding Proteins chemistry MeSH
- DNA chemistry MeSH
- Edetic Acid chemistry MeSH
- Nuclear Proteins chemistry MeSH
- Cadmium chemistry MeSH
- Cobalt chemistry MeSH
- Metals chemistry MeSH
- Humans MeSH
- Membrane Proteins chemistry MeSH
- Cell Line, Tumor MeSH
- Tumor Suppressor Proteins chemistry MeSH
- Tumor Suppressor Protein p53 chemistry MeSH
- Nickel chemistry MeSH
- Tumor Protein p73 MeSH
- Protein Structure, Tertiary MeSH
- Metals, Heavy chemistry MeSH
- Protein Binding MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- CKAP4 protein, human MeSH Browser
- Dithiothreitol MeSH
- DNA-Binding Proteins MeSH
- DNA MeSH
- Edetic Acid MeSH
- Nuclear Proteins MeSH
- Cadmium MeSH
- Cobalt MeSH
- Metals MeSH
- Membrane Proteins MeSH
- Tumor Suppressor Proteins MeSH
- Tumor Suppressor Protein p53 MeSH
- Nickel MeSH
- Tumor Protein p73 MeSH
- Metals, Heavy MeSH
- TP53 protein, human MeSH Browser
- TP73 protein, human MeSH Browser
Site-specific DNA recognition and binding activity belong to common attributes of all three members of tumor suppressor p53 family proteins: p53, p63 and p73. It was previously shown that heavy metals can affect p53 conformation, sequence-specific binding and suppress p53 response to DNA damage. Here we report for the first time that cadmium, nickel and cobalt, which have already been shown to disturb various DNA repair mechanisms, can also influence p63 and p73 sequence-specific DNA binding activity and transactivation of p53 family target genes. Based on results of electrophoretic mobility shift assay and luciferase reporter assay, we conclude that cadmium inhibits sequence-specific binding of all three core domains to p53 consensus sequences and abolishes transactivation of several promoters (e.g. BAX and MDM2) by 50μM concentrations. In the presence of specific DNA, all p53 family core domains were partially protected against loss of DNA binding activity due to cadmium treatment. Effective cadmium concentration to abolish DNA-protein interactions was about two times higher for p63 and p73 proteins than for p53. Furthermore, we detected partial reversibility of cadmium inhibition for all p53 family members by EDTA. DTT was able to reverse cadmium inhibition only for p53 and p73. Nickel and cobalt abolished DNA-p53 interaction at sub-millimolar concentrations while inhibition of p63 and p73 DNA binding was observed at millimolar concentrations. In summary, cadmium strongly inhibits p53, p63 and p73 DNA binding in vitro and in cells in comparison to nickel and cobalt. The role of cadmium inhibition of p53 tumor suppressor family in carcinogenesis is discussed.
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