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Query: UNIPROT:P06889 (Mol)
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Arsenic is a common environmental contaminant of our air, water and food, but not every individual who drinks arsenic-contaminated water shows clinical signs of toxicity. Large inter-individual variations are also found in arsenite-induced aneuploidy, chromosome aberrations and sister chromatid exchanges in peripheral blood lymphocytes from different human donors. Lymphoblasts are virally immortalized lymphocytes that retain most of the properties of lymphocytes. Individual lymphoblast cell lines retained their arsenite sensitivity after cryopreservation and subsequent revival. We measured the accumulation of 73[As]-arsenite into lymphoblast lines derived from 11 normal individuals. Arsenite accumulation rate varied 6.3 fold between the slowest and the fastest subjects. Assays in 14 lymphoblast lines showed variability to the toxic effects of arsenite, as measured by growth inhibition. Lymphoblast lines also vary with regard to their growth rates, but there is no relationship between growth rate and arsenite sensitivity. Surprisingly, we also found no correlation between arsenite accumulation rate and cellular sensitivity to growth inhibition, suggesting that the arsenite accumulation rate may not be the main determinant of cellular sensitivity to arsenic. We were also unable to detect evidence for a human homolog for the yeast arsenite efflux gene ACR3, using RT-PCR.
Mol Cell Biochem 2004 Jan
PMID:Variability in sensitivity to arsenite does not correlate with arsenic accumulation rate in normal human lymphoblasts. 1497 48

To protect human and ecosystem health, it is necessary to develop sensitive assays and to identify responsive cells and species (and their life stages). In this study, the relative genotoxicity of two inorganic arsenicals: trivalent sodium arsenite (As(3+)) and pentavalent sodium arsenate (As(5+)), was evaluated in two cell lines of phylogenetically different origin, using alkaline single-cell gel electrophoresis (i.e., the Comet assay) and the cytokinesis-block micronucleus (MN) assay. The cell lines were the rainbow trout gonad-2 (RTG-2) and Chinese hamster ovary-K1 (CHO-K1) lines. Following optimization and validation of both assays using reference chemicals (i.e., 1-100 microM hydrogen peroxide for the Comet assay and 1-10 mM ethylmethane sulfonate for the MN assay), cells were exposed to 1-10 microM of both arsenicals to determine the relative extent of genetic damage. The unexposed controls showed similar (background) levels of damage in both cell lines and for both assays. Treatment with the arsenicals induced concentration-dependent increases in genetic damage in the two cell lines. Arsenite was more potent than arsenate in inducing DNA strand breaks in the Comet assay; at the highest concentration (10 microM) arsenite produced similar levels of DNA damage in CHO-K1 and RTG-2 cells, while 10 microM arsenate was significantly more genotoxic in RTG-2 cells. MN induction was consistently higher in RTG-2 cells than in CHO-K1 cells, with 10 microM arsenite inducing an approximate 10-fold increase in both cell lines. MN induction also was positively correlated with DNA strand breaks for both arsenicals. Overall, the study demonstrated that the fish cells are more sensitive than the mammalian cells at environmentally realistic concentrations of both arsenicals, with arsenite being more toxic.
Environ Mol Mutagen 2004
PMID:Relative sensitivity of fish and mammalian cells to sodium arsenate and arsenite as determined by alkaline single-cell gel electrophoresis and cytokinesis-block micronucleus assay. 1519 50

Arsenic trioxide (As(2)O(3)) produces dramatic remissions in patients with relapsed or refractory acute promyelocytic leukemia. Its clinical use is burdened by QT prolongation, torsade de pointes, and sudden cardiac death. In the present study, we analyzed the molecular mechanisms leading to As(2)O(3)-induced abnormalities of cardiac electrophysiology. Using biochemical and electrophysiological methods, we show that long-term exposure to As(2)O(3) increases cardiac calcium currents and reduces surface expression of the cardiac potassium channel human ether-a-go-go-related gene (HERG) at clinically relevant concentrations of 0.1 to 1.5 microM. In ventricular myocytes, As(2)O(3) increases action potential duration measured at 30 and 90% of repolarization. As(2)O(3) interferes with hERG trafficking by inhibition of hERG-chaperone complexes and increases calcium currents by a faster cellular process. We propose that an increase in cardiac calcium current and reduced trafficking of hERG channels to the cell surface cause QT prolongation and torsade de pointes in patients treated with As(2)O(3). Our results suggest that calcium-channel antagonists will be useful in normalizing QT prolongation during As(2)O(3) therapy. As(2)O(3) is the first example of a drug that produces hERG liability by inhibition of ion-channel trafficking. Other drugs that interfere with proteins in the processing pathway of cardiac ion channels may be proarrhythmic for similar reasons.
Mol Pharmacol 2004 Jul
PMID:Mechanisms of arsenic-induced prolongation of cardiac repolarization. 1521 94

Arsenite is a human carcinogen that may induce cancer in skin, liver, kidney, bladder or lung. Arsenite executes its toxic effects by the induction of signaling cascades. In particular, the activation of the stress-induced protein kinase c-Jun N-terminal protein kinase and p38 and the phosphorylation and activation of the transcription factor c-Jun have been linked to the biological effects of arsenite. We analyzed whether arsenite has an impact on the biosynthesis of the zinc finger transcription factor Egr-1. Egr-1 transcription is upregulated following treatment of cells with hormones, cytokines or toxic chemicals, and thus Egr-1 integrates many signaling cascades with changes in gene expression patterns. Here, we show by Western blot experiments that arsenite induces a transient synthesis of Egr-1 in human HaCaT keratinocytes. Egr-1 biosynthesis was activated by arsenite concentrations insufficient for the induction of c-Jun biosynthesis. This arsenite-triggered Egr-1 biosynthesis was completely inhibited by the mitogen-activated protein kinase kinase inhibitor PD98059 and by AG1487, an epidermal growth factor (EGF) receptor-specific tyrosine kinase inhibitor. These results indicate that activation of the EGF receptor as well as stimulation of the mitogen activated/extracellular signal-regulated protein kinase is essential for arsenite-induced upregulation of Egr-1. Moreover, we detected an elevated transcriptional activation potential of the ternary complex factor Elk1, a key transcriptional regulator of serum response element-driven gene transcription. The Egr-1 5'-flanking region contains five serum response elements. Accordingly, we observed an increase in Egr-1 promoter activity as a result of arsenite treatment. The fact that low concentrations of arsenite are sufficient to induce Egr-1 biosynthesis suggests that Egr-1 may be an integral part of arsenite-triggered signaling cascades leading to tumor formation or cell death via alterations of the cellular genetic program.
J Mol Med (Berl) 2004 Aug
PMID:The zinc finger transcription factor Egr-1 is upregulated in arsenite-treated human keratinocytes. 1529 61

A question of major current interest is whether histone modification at a given gene correlates simply with transcriptional status or if distinctive modifications appear depending on how that gene is activated. The stress-inducible gene Hsp70 is activated by heat shock or by sodium arsenite. Heat shock produces acetylation of histone H4 at Hsp70 chromatin, whereas arsenite produces both H4 acetylation and H3 phosphorylation at the gene. Histone H3 remains markedly hypoacetylated at Hsp70 under these conditions. Arsenite, but not heat shock, requires signaling via p38 MAP kinase for Hsp70 induction and histone H3 phosphorylation. However, independently of p38 MAP kinase, both stresses strongly activate the transcription factor Hsf1. Using Hsf1-/- cells, we show that this factor is responsible for targeting histone H4 acetylation to Hsp70 chromatin. We establish here that histone modifications at inducible genes are not simply a reflection of transcriptional activity, but are strictly dependent on the stimulus used for induction.
Mol Cell 2004 Aug 27
PMID:Distinct stimulus-specific histone modifications at hsp70 chromatin targeted by the transcription factor heat shock factor-1. 1532 74

Cholesterol metabolism to pregnenolone is dependent on the steroidogenic acute regulatory protein (StAR), which activates mitochondrial transfer of cholesterol to cytochrome CYP450scc. In mouse Y-1 adrenal cells and testis MA10 cells stimulation by 8-Bromo-cAMP (Br-cAMP) is augmented by a novel signaling initiated by low concentrations of arsenite (3-20 microM) and anisomycin (0.2 microM), a more selective stress agent. Each elevated StAR mRNA (three-fold after 6 h treatment) even with simultaneous stimulation by Br-cAMP. Arsenite produced parallel increases in StAR protein expression and cholesterol metabolism, but not for P450scc-mediated metabolism of 20alpha-hydroxycholesterol. Although arsenite and anisomycin each stimulated the phosphorylation of p38, the p38 inhibitor SB203580 (SB) produced additive increases in StAR expression. Cholesterol metabolism increased in parallel but without the increased StAR protein phosphorylation produced by Br-cAMP. Arsenite and anisomycin each elevated StAR mRNA but preferentially increased the 3.5 kb form relative to the 1.6 kb form. Arsenite and anisomycin each enhanced the stability of the more labile 3.5 kb mRNA which contains AU-rich elements that control mRNA stability. Although there were increases in both forms of StAR mRNA, arsenite did not stimulate a StAR promoter-reporter that exhibited a typical three-fold response to Br-cAMP. Arsenite and anisomycin may therefore activate a novel SB-independent MAP kinase which in part increases StAR expression through stabilizing the 3.5 kb mRNA but which may also activate a mechanism that by-passes transcription factors detected by the reporter. SB stimulation, which was completely blocked by a MEK inhibitor, was also selective towards the 3.5 kb StAR mRNA suggesting a second pathway for mRNA stabilization. These activations contrast with inhibition of StAR expression by arsenite at higher concentrations or longer incubation times.
Mol Cell Endocrinol 2005 Feb 28
PMID:Novel signaling stimulated by arsenite increases cholesterol metabolism through increases in unphosphorylated steroidogenic acute regulatory (StAR) protein. 1571 39

Degeneration of dopaminergic neurons is one of the major features of Parkinson's disease. Many redox-active metals such as iron and manganese have been implicated in neuronal degeneration characterized by symptoms resembling Parkinson's disease. Even though, arsenic, which is another redox-active metal, has been shown to affect the central monoaminergic systems, but its potential in causing dopaminergic cell degeneration has not been fully known. Hence, the present study was designed to investigate arsenic signaling especially that is mediated by reactive oxygen species and its effect on early transcription factors in dopamine producing mesencephalic cell line 1RB3AN27. These mesencephalic cells were treated with low concentrations of sodium arsenite (0.1, 0.5, 1, 5, and 10 microM) and incubated for different periods of time (0-4 h). Arsenite was cytotoxic at 5 and 10 microM concentrations only after 72-h incubation period. Arsenite, in a dose-dependent manner, induced generation of reactive oxygen species (ROS) and activation of early transcription factors such as nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) as shown by electro mobility shift assay. Incubation of antioxidants, either N-acetyl-L-cysteine (50 microM) or alpha-tocopherol (50 microM) with 1 microM arsenite, suppressed ROS generation. Arsenite at 1 microM concentration was sufficient for maximal activation of NF-kappaB and AP-1 activation. Time kinetics studies showed maximal activation of NF-kappaB by 1 microM concentration of arsenite was seen at 120 min and correlated with complete degradation of Ikappa Balpha at 60 min. Similarly, maximal activation of AP-1 by 1 microM concentration of arsenite occurred at 120 min. N-acetyl-L-cysteine at 50 microM concentration inhibited arsenite-induced NF-kappa B and AP-1. In addition, arsenite was shown to induce phosphorylation of extracellular signal regulated kinase (ERK) 1/2 at concentrations of 1 microM and above. These results suggest that arsenite, at low and subcytoxic concentrations, appears to induce oxidative stress leading to activation of early transcription factors whereas addition of antioxidant inhibited the activation of these factors.
J Biochem Mol Toxicol 2005
PMID:Low levels of arsenite activates nuclear factor-kappaB and activator protein-1 in immortalized mesencephalic cells. 1584 23

The permeability transition pore (PTP) is central for apoptosis by acting as a good candidate pathway for the release of Cyt. c and apoptosis induction factors (AIF). Arsenite induces apoptosis via a direct effect on PTP. To characterize the exact mechanism for arsenite induces PTP opening, the effect of Ca2+ on As2O3-induced PTP opening, the relationship between As2O3-induced PTP opening and Cyt. c release from mitochondria and calcium-induced calcium release from mitochondria (mCICR), and the effects of As2O3 on Ca2+-induced PTP opening were studied. The results showed As2O3 induces Cyt. c release by triggering PTP opening. Ca2+ is necessary for As2O3-induced PTP opening. As2O3-induced PTP opening and Cyt. c release depends on mCICR. As2O3 promotes PTP opening by lowering Ca2+-threshold. These results indicated As2O3 induce Cyt. c release from mitochondria by lowering Ca2+-threshold for PTP and triggering mCICR-dependent PTP opening. Suggesting that it is possible to control apoptosis by altering Ca2+ threshold and mCICR to modulate PTP opening and Cyt. c release.
Mol Cell Biochem 2005 Sep
PMID:mCICR is required for As2O3-induced permeability transition pore opening and cytochrome c release from mitochondria. 1613 12

Epidemiologic investigations demonstrated that arsenite exposure increases the risk of various human cancers, including skin, lung, bladder, and kidney cancers. However, oral administration of arsenite alone has failed to induce tumors in animal models, suggesting that arsenic may act to enhance mutagenicity induced by other carcinogens. Arsenite may function as a co-carcinogen, acting by inhibiting repair of carcinogen-induced DNA damage mediated by p53 and p21, a p53 target gene. To elucidate the interaction between arsenite and p53 tumor suppressor protein, we studied the effect of arsenite on ultraviolet B (UVB)-induced p53 phosphorylation, p53 DNA binding activity, and p53-induced target gene transactivation in the JB6 Cl41 mouse epidermal skin cell model. Our results indicated that arsenite suppressed UVB-induced p53 phosphorylation and p53 DNA binding activity. Arsenite also inhibited casein kinase 2 (CK2) activity and decreased p53-regulated p21 protein expression. These data suggest that the direct inhibition of p53 functional activation is one of the mechanisms through which arsenite interferes with p53 function, and thus may be a significant mechanism for the co-carcinogenic effects of arsenite.
Mol Carcinog 2006 Nov
PMID:Arsenite inhibits p53 phosphorylation, DNA binding activity, and p53 target gene p21 expression in mouse epidermal JB6 cells. 1673 26

Arsenic is widely distributed in nature and all organisms possess regulatory mechanisms to evade toxicity and acquire tolerance. Yet, little is known about arsenic sensing and signaling mechanisms or about their impact on tolerance and detoxification systems. Here, we describe a novel role of the S. cerevisiae mitogen-activated protein kinase Hog1p in protecting cells during exposure to arsenite and the related metalloid antimonite. Cells impaired in Hog1p function are metalloid hypersensitive, whereas cells with elevated Hog1p activity display improved tolerance. Hog1p is phosphorylated in response to arsenite and this phosphorylation requires Ssk1p and Pbs2p. Arsenite-activated Hog1p remains primarily cytoplasmic and does not mediate a major transcriptional response. Instead, hog1delta sensitivity is accompanied by elevated cellular arsenic levels and we demonstrate that increased arsenite influx is dependent on the aquaglyceroporin Fps1p. Fps1p is phosphorylated on threonine 231 in vivo and this phosphorylation critically affects Fps1p activity. Moreover, Hog1p is shown to affect Fps1p phosphorylation. Our data are the first to demonstrate Hog1p activation by metalloids and provides a mechanism by which this kinase contributes to tolerance acquisition. Understanding how arsenite/antimonite uptake and toxicity is modulated may prove of value for their use in medical therapy.
Mol Biol Cell 2006 Oct
PMID:The MAPK Hog1p modulates Fps1p-dependent arsenite uptake and tolerance in yeast. 1688 17


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