Cadmium induces conformational modifications of wild-type p53 and suppresses p53 response to DNA damage in cultured cells.
The p53 tumor suppressor protein is a transcription factor that binds DNA in a sequence-specific manner through a protein domain stabilized by the coordination of zinc within a tetrahedral cluster of three cysteine residues and one histidine residue. We show that cadmium, a metal that binds thiols with high affinity and substitutes for zinc in the cysteinyl clusters of many proteins, inhibits the binding of recombinant, purified murine p53 to DNA. In human breast cancer MCF7 cells (expressing wild-type p53), exposure to cadmium (5-40 microM) disrupts native (wild-type) p53 conformation, inhibits DNA binding, and down-regulates transcriptional activation of a reporter gene. Cadmium at 10-30 microM impairs the p53 induction in response to DNA-damaging agents such as actinomycin D, methylmethane sulfonate, and hydrogen peroxide. Exposure to cadmium at 20 microM also suppresses the p53-dependent cell cycle arrest in G(1) and G(2)/M phases induced by gamma-irradiation. These observations indicate that cadmium at subtoxic levels impairs p53 function by inducing conformational changes in the wild-type protein. There is evidence that cadmium is carcinogenic to humans, in particular for lung and prostate, and cadmium is known to accumulate in several organs. This inhibition of p53 function could play a role in cadmium carcinogenicity.
Méplan
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International Agency for Research on Cancer, Unit of Mechanisms of Carcinogenesis, 150 Cours Albert Thomas, 69372 Lyon cedex 08, France.
Mann
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Hainaut
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D000818:Animals; D001692:Biological Transport; D001943:Breast Neoplasms / Q000378:metabolism; D019256:Cadmium Chloride / Q000494:pharmacology*; D002451:Cell Compartmentation; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage; D015536:Down-Regulation; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D005720:Gamma Rays; D006801:Humans; D008668:Metallothionein / Q000096:biosynthesis; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D011994:Recombinant Proteins / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics
D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D008668:Metallothionein; D019256:Cadmium Chloride