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J Biol Chem, Vol. 274, Issue 44, 31663-31670, October 29, 1999
,
From the 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 µM) disrupts native
(wild-type) p53 conformation, inhibits DNA binding, and down-regulates
transcriptional activation of a reporter gene. Cadmium at 10-30
µM impairs the p53 induction in response to DNA-damaging
agents such as actinomycin D, methylmethane sulfonate, and hydrogen
peroxide. Exposure to cadmium at 20 µM also suppresses
the p53-dependent cell cycle arrest in G1 and
G2/M phases induced by International Agency for Research on Cancer,
Unit of Mechanisms of Carcinogenesis, 150 Cours Albert Thomas, 69372 Lyon cedex 08, France and the ¶ University of Alaska,
Anchorage, Alaska 99508
-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.
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