Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The generalized process of mRNA decay involves deadenylation followed by release from translating polysomes, decapping, and exonuclease decay of the mRNA body. In contrast the mRNA endonuclease PMR1 forms a selective complex with its translating substrate mRNA, where it initiates decay by cleaving within the mRNA body. In stressed cells the phosphorylation of the alpha subunit of eukaryotic initiation factor 2 causes translating mRNAs to accumulate with stalled 48S subunits in large subcellular structures termed stress granules (SGs), wherein mRNAs undergo sorting for reinitiation, storage, or decay. Given the unique relationship between translation and PMR1-mediated mRNA decay, we examined the impact of stress-induced dissociation of polysomes on this process. Arsenite stress disrupts the polysome binding of PMR1 and its substrate mRNA but has no impact on the critical tyrosine phosphorylation of PMR1, its association with substrate mRNA, or its association with the functional approximately 680-kDa mRNP complex in which it normally resides on polysomes. We show that arsenite stress drives PMR1 into an RNase-resistant complex with TIA-1, and we identify a distinct domain in the N terminus of PMR1 that facilitates its interaction with TIA-1. Finally, we show that arsenite promotes the delayed association of PMR1 with SGs under conditions which cause tristetraprolin and butyrate response factor 1, proteins that facilitate exonucleolytic mRNA, to exit SGs.
Mol Cell Biol 2006 Dec
PMID:Polysome-bound endonuclease PMR1 is targeted to stress granules via stress-specific binding to TIA-1. 1698 78

Arsenic trioxide (As(2)O(3)) exhibits important antitumor activities in vitro and in vivo, but the precise mechanisms by which it induces its effects are not known. We provide evidence that during treatment of BCR-ABL-expressing cells with As(2)O(3), there is activation of a cellular pathway involving the p70 S6 kinase (p70S6K). Our data show that p70S6K is rapidly phosphorylated on Thr(421) and Ser(424) and is activated in an As(2)O(3)-inducible manner. The mammalian target of rapamycin (mTOR) is also phosphorylated/activated in an As(2)O(3)-inducible manner, and its activity is required for downstream engagement of p70S6K. p70S6K subsequently phosphorylates the S6 ribosomal protein on Ser(235)/Ser(236) and Ser(240)/Ser(244) to promote initiation of mRNA translation. Treatment of chronic myelogenous leukemia-derived cell lines with As(2)O(3) also results in phosphorylation of the 4E-BP1 repressor of mRNA translation on Thr(37)/Thr(46) and Thr(70), sites required for its deactivation and its dissociation from the eukaryotic initiation factor 4E complex to allow cap-dependent mRNA translation. In studies to determine the functional relevance of this pathway, we found that inhibition of mTOR and downstream cascades enhances induction of apoptosis by As(2)O(3). Consistent with this, the mTOR inhibitor rapamycin strongly potentiated As(2)O(3)-mediated suppression of primitive leukemic progenitors from the bone marrow of chronic myelogenous leukemia patients. Altogether, our data show that the mTOR/p70S6K pathway is activated in a negative feedback regulatory manner in response to As(2)O(3) in BCR-ABL-transformed cells and plays a key regulatory role in the induction of anti-leukemic responses.
Mol Cancer Ther 2006 Nov
PMID:Activation of mammalian target of rapamycin and the p70 S6 kinase by arsenic trioxide in BCR-ABL-expressing cells. 1712 28

Arsenic is an environmental pollutant capable of causing oxidative stress, disturbance of metabolism, and cancer development. The present study was undertaken to investigate the effects of exposure to sodium arsenite on the glutathione pool, lipid peroxidation, protein carbonyl levels, global DNA methylation, and activities of six antioxidant enzymes in goldfish liver. In a preliminary experiment, 7-day exposure to 200 microM sodium arsenite, but not 10 or 100 microM, disturbed the glutathione status. A detailed investigation of oxidative stress development and antioxidant responses was further examined during different periods of exposure to 200 microM sodium arsenite. This treatment increased lipid peroxide levels after 1 and 4 days of exposure but did not affect thiobarbituric acid reactive substances and protein carbonyls. Oxidized glutathione and the oxidative stress index rose after 4 days, but de novo glutathione synthesis decreased both parameters after 7 days. Activities of the main antioxidant enzymes-superoxide dismutase, catalase, and glutathione peroxidase, were elevated after longer periods of exposure, indicating an enhanced antioxidant response. Arsenite exposure led to DNA hypomethylation, which is an early marker of disturbed epigenetic regulations. The findings suggest that goldfish livers cope with arsenic-induced oxidative stress mainly through adaptive changes in the glutathione pool and antioxidant enzymes.
Environ Mol Mutagen 2007 Oct
PMID:Oxidative stress and antioxidant defenses in goldfish liver in response to short-term exposure to arsenite. 1768 60

Arsenite is a human carcinogen causing skin, bladder, and lung tumors, but the cellular mechanisms underlying these effects remain unclear. We investigated expression of the essential base excision DNA repair enzyme apurinic endonuclease 1 (Ape1) in response to sodium arsenite. In mouse 10T(1/2) fibroblasts, Ape1 induction in response to arsenite occurred about equally at the mRNA, protein, and enzyme activity levels. Analysis of the APE1 promoter region revealed an AP-1/CREB binding site essential for arsenite-induced transcriptional activation in both mouse and human cells. Electrophoretic mobility shift assays indicated that an ATF4/c-Jun heterodimer was the responsible transcription factor. RNA interference targeting c-Jun or ATF4 eliminated arsenite-induced APE1 transcription. Suppression of Ape1 or ATF4 sensitized both mouse fibroblasts (10T(1/2)) and human lymphoblastoid cells (TK6) to arsenite cytotoxicity. Expression of Ape1 from a transgene did not efficiently restore arsenite resistance in ATF4-depleted cells but did offset initial accumulation of abasic DNA damage following arsenite treatment. Mutagenesis by arsenite (at the TK and HPRT loci in TK6 cells) was observed only for ATF4-depleted cells, which was strongly offset by Ape1 expression from a transgene. Therefore, the ATF4-mediated up-regulation of Ape1 and other genes plays a key role against arsenite-mediated toxicity and mutagenesis.
Mol Cell Biol 2007 Dec
PMID:ATF4-dependent oxidative induction of the DNA repair enzyme Ape1 counteracts arsenite cytotoxicity and suppresses arsenite-mediated mutagenesis. 1793 2

Arsenic trioxide (ATO) has been recommended for the treatment of refractory cases of acute promyelocytic leukemia (APL). Recent studies in our laboratory indicated that oxidative stress plays a key role in ATO-induced cytotoxicity in human leukemia (HL-60) cells. In the present investigation, we performed the MTT assay and trypan blue exclusion test for cell viability. We also performed the thiobarbituric acid test to determine the levels of malondialdehyde (MDA) production in HL-60 cells coexposed to either ascorbic acid (AA) and ATO or to n-acetyl-L-cysteine (NAC) and ATO. The results of MTT assay indicated that AA exposure potentiates the cytotoxicity of ATO in HL-60 cells, as evidenced by a gradual increase in MDA levels with increasing doses of AA. In contrary, the addition of NAC to ATO-treated HL-60 cells resulted in a dose-dependent decrease of MDA production. From these results, we conclude that the addition of the AA to ATO-treated HL-60 cells enhances the formation of reactive oxygen species (ROS), whereas the addition of NAC under the same experimental condition significantly (p < .05) decreases the level of ROS formation. On the basis of these direct in vitro findings, our studies provide evidence that AA may extend the therapeutic spectrum of ATO. The coadministration of NAC with ATO shows a potential specificity for tumor cells, indicating that it may not enhance the clinical outcome associated with ATO monotherapy in vivo.
J Biochem Mol Toxicol
PMID:Differential effect of ascorbic acid and n-acetyl-L-cysteine on arsenic trioxide-mediated oxidative stress in human leukemia (HL-60) cells. 1841 92

Arsenite has been reported to exert dose-dependent dual effects: triggering apoptosis at relatively high concentrations, whereas inducing partial differentiation at low concentrations in leukemia cells. However, the relevant molecular mechanisms of its action at low and nonapoptotic concentrations remain to be elucidated. We examined the effect of arsenite on activation of key transcription factors in cultured U937 human monocytes/macrophages. Electrophoretic mobility shift assay (EMSA), protein/DNA array and luciferase reporter assay were used to analyze the effect of arsenite on the functional activities of transcription factors. Protein/DNA array analysis showed that activation of E2F was seen after 6-h exposure to 1 and 10 microM arsenite. In contrast, activation of NF-kappaB took place only at 1 microM arsenite, whereas 10 microM arsenite showed no recognizable effect on this nuclear transcription factor in the protein/DNA array analysis. EMSA using a NF-kappaB consensus probe indicates the functional activation of RelB/p50 in the presence of 1 microM arsenite, confirming the above results. Luciferase reporter assay for NF-kappaB showed activation of NF-kappaB in the presence of 1 microM arsenite. Interleukin (IL)-8 and B-cell-activating factor of the tumor necrosis factor family (BAFF) mRNA expression, which have been shown to be regulated through NF-kappaB, were activated in the presence of 1 microM arsenite. These results support the hypothesis that the primary action of nonapoptotic concentrations of arsenite in this cell line is activation of NF-kappaB, signaling as a decision maker for end results such as inflammation disease or cancer. This finding offers the possibility of providing a logical explanation for the observations made by many scientists that chronic exposure of human populations to low doses of arsenic is significantly correlated to clinical signs of inflammation in many tissues.
J Biochem Mol Toxicol
PMID:Selective activation of NF-kappaB and E2F by low concentration of arsenite in U937 human monocytic leukemia cells. 1841 99

Arsenic trioxide (ATO) can affect many biological functions such as apoptosis and differentiation in various cells. We investigated the involvement of ROS and GSH in ATO-induced HeLa cell death using ROS scavengers, especially N-acetylcysteine (NAC). ATO increased intracellular O(2)(*-) levels and reduced intracellular GSH content. The ROS scavengers, Tempol, Tiron and Trimetazidine, did not significantly reduce levels of ROS or GSH depletion in ATO-treated HeLa cells. Nor did they reduce the apoptosis induced by ATO. In contrast, treatment with NAC reduced ROS levels and GSH depletion in the ATO-treated HeLa cells and prevented ATO-induced apoptosis. Treatment with exogenous SOD and catalase reduced the depletion of GSH content in ATO-treated cells. Catalase strongly protected the cells from ATO-induced apoptosis. In addition, treatment with SOD, catalase and NAC slightly inhibited the G1 phase accumulation induced by ATO. In conclusion, NAC protects HeLa cells from apoptosis induced by ATO by up-regulating intracellular GSH content and partially reducing the production of O(2)(*-).
Mol Cells 2008 Jul 31
PMID:Suppression of arsenic trioxide-induced apoptosis in HeLa cells by N-acetylcysteine. 1851 84

Arsenic trioxide (As2O3) is used clinically to treat acute promyelocytic leukemia but is less successful in other malignancies. To identify targets for potential combination therapies, we have begun to characterize signaling pathways leading to As2O3-induced cytotoxicity. Previously, we described the requirement for a reactive oxygen species-mediated, SEK1/c-Jun NH2-terminal kinase (JNK) pathway to induce apoptosis. AKT inhibits several steps in this pathway; therefore, we postulated that As2O3 might decrease its activity. Indeed, As2O3 decreases not only AKT activity but also total AKT protein, and sensitivity to As2O3 correlates with the degree of AKT protein decrease. Decreased AKT expression further correlates with JNK activation and the release of AKT from the JNK-interacting protein 1 scaffold protein known to assemble the mitogen-activated protein kinase cascade. We found that As2O3 regulates AKT protein stability without significant effects on its transcription or translation. We show that As2O3 decreases AKT protein via caspase-mediated degradation, abrogated by caspase-6, caspase-8, caspase-9, and caspase-3 inhibitors but not proteosome inhibitors. Furthermore, As2O3 enhances the ability of a heat shock protein 90 inhibitor to decrease AKT expression and increase growth inhibition. This suggests that As2O3 may be useful in combination therapies that target AKT pathways or in tumors that have constitutively active AKT expression.
Mol Cancer Ther 2008 Jun
PMID:Arsenic trioxide decreases AKT protein in a caspase-dependent manner. 1856 39

Arsenic trioxide (ATO) affects many biological processes such as cell proliferation, apoptosis, differentiation and angiogenesis. L-buthionine sulfoximine (BSO) is an inhibitor of GSH synthesis. We tested whether ATO reduced the viability of lung cancer A549 cells in vitro, and investigated the in vitro effect of the combination of ATO and BSO on cell viability in relation to apoptosis and the cell cycle. ATO caused a dose-dependant decrease of viability of A549 cells with an IC50 of more than 50 microM. Low doses of ATO or BSO (1 approximately 10 microM) alone did not induce cell death. However, combined treatment depleted GSH content and induced apoptosis, loss of mitochondrial transmembrane potential (DeltaPsi(m)) and cell cycle arrest in G2. Reactive oxygen species (ROS) increased or decreased depending on the concentration of ATO. In addition, BSO generally increased ROS in ATO-treated A549 cells. ROS levels were at least in part related to apoptosis in cells treated with ATO and/or BSO. In conclusion, we have demonstrated that A549 lung cells are very resistant to ATO, and that BSO synergizes with clinically achievable concentration of ATO. Our results suggest that combination treatment with ATO and BSO may be useful for treating lung cancer.
Mol Cells 2008 Aug 31
PMID:Induction of apoptosis in arsenic trioxide-treated lung cancer A549 cells by buthionine sulfoximine. 1859 14

Environmental sodium arsenite is a toxin that is associated with male infertility due to decreased and abnormal sperm production. Arsenic trioxide (ATO), another inorganic trivalent semimetal, is an effective therapy for acute promyelocytic leukemia, and there is investigation of its possible efficacy in prostate cancer. However, the mechanism of arsenic action in male urogenital tract tissues is not clear. Because the androgen receptor (AR) plays an important role in spermatogenesis and prostate cancer, we explored the possibility that trivalent arsenic regulates AR function. We found that arsenic inhibited AR transcriptional activity in prostate cancer and Sertoli cells using reporter gene assays testing several androgen response element-containing regions and by assessing native target gene expression. Arsenic inhibition of AR activity was not due to down-regulation of AR protein levels, decreased hormone binding to AR, disruption of AR nuclear translocation, or interference with AR-DNA binding in vitro. However, chromatin immunoprecipitation studies revealed that arsenic inhibited AR recruitment to an AR target gene enhancer in vivo. Consistent with a deficiency in AR-chromatin binding, arsenic disrupted AR amino and carboxyl termini interaction. Furthermore, ATO caused a significant decrease in prostate cancer cell proliferation that was more pronounced in cells expressing AR compared with cells depleted of AR. In addition, inhibition of AR activity by ATO and by the AR antagonist, bicalutamide, was additive. Thus, arsenic-induced male infertility may be due to inhibition of AR activity. Further, because AR is an important target in prostate cancer therapy, arsenic may serve as an effective therapeutic option.
Mol Endocrinol 2009 Mar
PMID:Inhibition of androgen receptor transcriptional activity as a novel mechanism of action of arsenic. 1913 11


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