Toxicogenomic effect of nickel and beyond

Yao, Yixin; Costa, Max

doi:10.1007/s00204-014-1313-8

Cited by 26 publications

(20 citation statements)

References 32 publications

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“…The actual mechanisms of nickel toxicity and carcinogenicity are yet to be elucidated, despite the many hypotheses presented in the literature. Reactive oxygen species production, DNA repair inhibition, and hypoxic stress induction are among the most popular ones . Ni(II) ions hydrolyze peptide bonds preceding Ser/Thr‐Xaa‐His sequences (where Xaa is any amino acid except Pro, Scheme ) .…”

Section: Introductionmentioning

confidence: 99%

“…Reactive oxygen species production, DNA repair inhibition, and hypoxic stress induction are among the most popular ones. [12,[19][20][21] Ni(II) ions hydrolyze peptide bonds preceding Ser/Thr-Xaa-His sequences (where Xaa is any amino acid except Pro, Scheme 1). [22] Such sequences occur in many proteins, with those in flexible parts exposed on the protein surface most prone to cleavage.…”

Section: Introductionmentioning

confidence: 99%

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Peptide Bond Cleavage by Ni(II) Ions within the Nuclear Localization Signal Sequence

Frączyk

Bonna

Stefaniak

et al. 2020

Chemistry & Biodiversity

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Nickel is harmful to humans, being both carcinogenic and allergenic. However, the mechanisms of this toxicity are still unresolved. We propose that Ni(II) ions disintegrate proteins by hydrolysis of peptide bonds preceding the Ser/Thr‐Xaa‐His sequences. Such sequences occur in nuclear localization signals (NLSs) of human phospholipid scramblase 1, Sam68‐like mammalian protein 2, and CLK3 kinase. We performed spectroscopic experiments showing that model nonapeptides derived from these NLSs bind Ni(II) at physiological pH. We also proved that these sequences are prone to Ni(II) hydrolysis. Thus, the aforementioned NLSs may be targets for nickel toxicity. This implies that Ni(II) ions disrupt the transport of some proteins from cytoplasm to cell nucleus.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Peptide Bond Cleavage by Ni(II) Ions within the Nuclear Localization Signal Sequence

Frączyk

Bonna

Stefaniak

et al. 2020

Chemistry & Biodiversity

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“…Previously, we reported on tungsten's ability to induce cancer‐related endpoints including cell transformation, increased migration, xenograft growth in nude mice, and the activation of multiple cancer‐related pathways, following in vitro exposure to BEAS‐2B cells . Histone modifications have been identified following exposure to a number of other carcinogenic metals . Here, we show perturbations in the levels of global histone methylation that occur after tungstate exposure and suggest mechanisms that mediate this effect involving the ability of tungstate to selectively degrade the histone demethylase dioxygenases.…”

Section: Introductionmentioning

confidence: 52%

Tungsten exposure causes a selective loss of histone demethylase protein

Laulicht-Glick

Zhang

et al. 2017

Molecular Carcinogenesis

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In the course of our investigations into the toxicity of tungstate, we discovered that cellular exposure resulted in the loss of the histone demethylase protein. We specifically investigated the loss of two histone demethylase dioxygenases, JARID1A and JMJD1A. Both of these proteins were degraded in the presence of tungstate and this resulted in increased global levels of H3K4me3 and H3K9me2, the substrates of JARID1A and JMJD1A respectively. Treatment with MG132 completely inhibited the loss of the demethylase proteins induced by tungstate treatment, suggesting that tungstate activated the proteasomal degradation of these proteins. The changes in global histone marks and loss of histone demethylase protein persisted for at least 48 hours after removing sodium tungstate from the culture. The increase in global histone methylation remained when cells were cultured in methionine-free media, indicating that the increased histone methylation did not depend upon any de novo methylation process, but rather was due to the loss of the demethylase protein. Similar increases of H3K4me3 and H3K9me2 were observed in the livers of the mice that were acutely exposed to tungstate via their drinking water. Taken together, our results indicated that tungstate exposure specifically reduced histone demethylase JARID1A and JMJD1A via proteasomal degradation, leading to increased histone methylation.

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“…Ni has tested nonmutagenic in various biological assays, which is consistent with its inability to form DNA adducts or DNA breaks in contrast to genotoxic metals such as chromium(VI) (DeLoughery et al, 2015; Reynolds et al, 2004). Carcinogenicity of Ni has been attributed to its epigenetic effects in chromatin and chronic activation of transcription factors that are frequently altered in cancer cells (Costa et al, 2005; Salnikow and Zhitkovich, 2008; Yao and Costa, 2014). Ni(II) ions act as hypoxia mimics causing a massive accumulation of HIF-1α and inducing a hypoxia-like transcription response (Salnikow et al, 2000, 2003).…”

Section: Introductionmentioning

confidence: 99%

Nickel-induced HIF-1α promotes growth arrest and senescence in normal human cells but lacks toxic effects in transformed cells

Łuczak

Zhitkovich

2017

Toxicology and Applied Pharmacology

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Nickel is a human carcinogen that acts as a hypoxia mimic by activating the transcription factor HIF-1α and hypoxia-like transcriptomic responses. Hypoxia and elevated HIF-1α are typically associated with drug resistance in cancer cells, which is caused by increased drug efflux and other mechanisms. Here we examined the role of HIF-1α in uptake of soluble Ni(II) and Ni(II)-induced cell fate outcomes using si/shRNA knockdowns and gene deletion models. We found that HIF-1α had no effect on accumulation of Ni(II) in two transformed (H460, A549) and two normal human cell lines (IMR90, WI38). The loss of HIF-1α also produced no significant impact on p53-dependent and p53-independent apoptotic responses or clonogenic survival of Ni(II)-treated transformed cells. In normal human cells, HIF-1α enhanced the ability of Ni(II) to inhibit cell proliferation and cause a permanent growth arrest (senescence). Consistent with its growth-suppressive effects, HIF-1α was important for upregulation of the cell cycle inhibitors p21 (CDKN1A) and p27 (CDKN1B). Irrespective of HIF-1α status, Ni(II) strongly increased levels of MYC protein but did not change protein expression of the cell cycle-promoting phosphatase CDC25A or the CDK inhibitor p16. Our findings indicate that HIF-1α limits propagation of Ni(II)-damaged normal cells, suggesting that it may act in a tumor suppressor-like manner during early stages of Ni(II) carcinogenesis.

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Toxicogenomic effect of nickel and beyond

Cited by 26 publications

References 32 publications

Peptide Bond Cleavage by Ni(II) Ions within the Nuclear Localization Signal Sequence

Peptide Bond Cleavage by Ni(II) Ions within the Nuclear Localization Signal Sequence

Tungsten exposure causes a selective loss of histone demethylase protein

Nickel-induced HIF-1α promotes growth arrest and senescence in normal human cells but lacks toxic effects in transformed cells

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