Divalent metal ions induce conformational change in pure, human wild-type p53 tumor suppressor protein

Coffer, Arnold I.; Knowles, Phillip P.

doi:10.1016/0167-4838(94)90197-x

Cited by 20 publications

(12 citation statements)

References 20 publications

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“…39 It was reported that Zn 2 in solution can alter the conformation of p53 by binding to the protein. 40 p53-DNA interactions may also be very sensitive to the DNA topology, 41 which is also affected by the ion concentration. The effect of Mg 2 on p53-DNA interaction has not been systematically investigated, though it has been reported that the p53 core domain was rarely observed bound to supercoiled DNA at a Mg 2 concentration higher than 0.5 mM.…”

Section: Discussion Dilemma Of Using Divalent Cationsmentioning

confidence: 99%

Dynamic interactions of p53 with DNA in solution by time-lapse atomic force microscopy

Cherny

Heim

et al. 2001

Journal of Molecular Biology

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Section: Discussion Dilemma Of Using Divalent Cationsmentioning

confidence: 99%

Dynamic interactions of p53 with DNA in solution by time-lapse atomic force microscopy

Cherny

Heim

et al. 2001

Journal of Molecular Biology

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“…The loss of Zn 2þ may affect conformation and DNA binding activity both in mutant and normal p53 [Hainaut and Milner, 1993;Coffer and Knowles, 1994;Butler and Loh, 2003]. The lowest effect of ELF was seen in H1299tTA-His175, which has a p53 mutation that substantially accelerates the rate of Zn 2þ loss and where p53 probably exists in the cell primarily in the folded zinc-free state [Butler and Loh, 2003].…”

Section: Possible Mechanismsmentioning

confidence: 99%

Exposure to ELF magnetic field tuned to Zn inhibits growth of cancer cells

Sarimov

Markovà

Johansson

et al. 2005

Bioelectromagnetics

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The effects of ELF alternating magnetic fields tuned to Zn(2+) on the growth of cancer cells with different status of p53 were investigated using a cell proliferation assay. Human cancer cells HeLa (cervix cancer, p53(+/+)), Saos-2 and Saos-2-His-273 (osteosarcoma, p53(-/-) and p53 His-273 mutant, respectively), H1299tTA and H1299tTA-His175 (lung carcinoma, p53(-/-) and p53 His-175 mutant), and normal human fibroblasts VH-10 (p53(+/+)) were used. Exposure parameters were calculated for the first harmonic of Zn(2+) based either on the magnetic parametric resonance (MPR) model of Lednev or the ion parametric resonance (IPR) model of Blanchard and Blackman. ELF exposure was for 72 and 96 h. The vertical alternating field was 20 Hz at amplitudes of either 38.7 or 77.4 microT (peaks, IPR or MPR, respectively). The vertical static magnetic field was 43 microT, and the horizontal static magnetic field was zeroed. Treatments of cells with PRIMA-1 and gamma-rays were used as positive controls. Growth inhibition was observed in cells after exposure to ELF at 38.7 microT. Inhibition of HeLa, VH-10, and Saos-2-His-273 cells was statistically significant, P=0.0003, 0.02, and 0.006, respectively. No consistent ELF effects following exposure 77.4 microT were seen. PRIMA-1 inhibited the growth of all cell lines with the strongest effect in mutant p53-carrying cell line H1299tTA-His175. The effects of gamma-rays were relatively weak, suggesting that the cell proliferation assay under conditions employed in this study is not very sensitive to apoptosis. In conclusion, ELF under conditions of exposure tuned to Zn(2+) according to the IPR model inhibited the growth of cancer and normal cells. No clear relationship of the observed growth inhibition to p53 status was found. Further experiments, using complementary techniques, are required to test whether p53 reactivation by ELF is feasible.

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“…Reduction of cysteines stimulates p53 DNAbinding (5,15,50), and Ref-1, a protein that regulates the redox state of several transcription factors, is a potent activator of p53 (51). In vitro, the conformation and DNA-binding capacity of p53 are altered by incubation with metals chemically close to zinc, such as cadmium and copper, but not with cobalt, magnesium, manganese, or iron (17,52). These observations have led to the suggestion that specific metals and redox factors may affect the fine tuning of p53 and participate in the physiological control of p53 functions (5, 16, 51, 53).…”

Section: Discussionmentioning

confidence: 99%

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

Méplan

Mann

Hainaut

1999

Journal of Biological Chemistry

181

102

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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 M) disrupts native (wild-type) p53 conformation, inhibits DNA binding, and down-regulates transcriptional activation of a reporter gene. Cadmium at 10 -30 M impairs the p53 induction in response to DNA-damaging agents such as actinomycin D, methylmethane sulfonate, and hydrogen peroxide. Exposure to cadmium at 20 M also suppresses the p53-dependent cell cycle arrest in G 1 and G 2 /M phases induced by ␥-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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Divalent metal ions induce conformational change in pure, human wild-type p53 tumor suppressor protein

Cited by 20 publications

References 20 publications

Dynamic interactions of p53 with DNA in solution by time-lapse atomic force microscopy

Dynamic interactions of p53 with DNA in solution by time-lapse atomic force microscopy

Exposure to ELF magnetic field tuned to Zn inhibits growth of cancer cells

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

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