Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P16104 (H2AX)
 3,930 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arsenic compounds, which are well-documented human carcinogens, are now used in cancer therapy. Knowledge of the mechanism by which arsenic exerts its toxicity may help in designing a more effective regimen for therapy. In this study, we showed that arsenite could induce prominent mitotic arrest in CGL-2 cells and demonstrated the presence of damaged DNA in arsenite-arrested mitotic cells. We then explored why these cells with arsenite-induced DNA damage were arrested at mitosis instead of G2 stage. When synchronized CGL-2 cells were treated with arsenite at stage G1, S or G2, all progressed into, and arrested at, the mitotic stage and contained damaged DNA, as demonstrated by the appearance of the DNA double-strand break marker, phosphorylated histone H2A.X (gamma-H2AX). Since X-irradiation induced G2 arrest in CGL-2 cells, these cells clearly have a functional G2 DNA damage checkpoint. However, treatment of X-irradiated CGL-2 cells with arsenite resulted in a decrease in G2 cells and an increase in mitotic cells, suggesting that arsenite may inhibit activation of the G2 DNA damage checkpoint and thus allow cells with damaged DNA to proceed from G2 into mitosis. Immunoblot analysis confirmed that arsenite treatment reduced the X-irradiation-induced phosphorylation of both ataxia-telangiectasia, mutated at serine 1981 and Cdc25C at serine 216, events which are crucial for G2 checkpoint activation and G2 arrest. Moreover, a higher frequency of apoptotic cells is observed in mitotic CGL-2 cells arrested by arsenite than those arrested by nocodazole or taxol. Our results show that the combined effects of arsenite in inducing DNA damages, inhibiting the activation of G2 checkpoint, and arresting cells with damaged DNA in the mitotic stage may subsequently enhance the induction of apoptosis in arsenite-arrested mitotic CGL-2 cells.
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PMID:Arsenite induces prominent mitotic arrest via inhibition of G2 checkpoint activation in CGL-2 cells. 1547 1

Cigarette smoke (CS) is a major risk factor for cardiovascular and lung diseases. Because CS is a complex aerosol containing more than 7,000 chemicals it is challenging to assess the contributions of individual constituents to its overall toxicity. Toxicological profiles of individual constituents as well as mixtures can be however established in vitro, by applying high through-put screening tools, which enable the profiling of Harmful and Potentially Harmful Constituents (HPHCs) of tobacco smoke, as defined by the U.S. Food and Drug Administration (FDA). For an initial assessment, an impedance-based instrument was used for a real-time, label-free assessment of the compound's toxicity. The instrument readout relies on cell adhesion, viability and morphology that all together provide an overview of the cell status. A dimensionless parameter, named cell index, is used for quantification. A set of different staining protocols was developed for a fluorescence imaging-based investigation and a HCS platform was used to gain more in-depth information on the kind of cytotoxicity elicited by each HPHC. Of the 15 constituents tested, only five were selected for HCS-based analysis as they registered a computable LD50 (< 20 mM). These included 1-aminonaphtalene, Arsenic (V), Chromium (VI), Crotonaldehyde and Phenol. Based on their effect in the HCS, 1-aminonaphtalene and Phenol could be identified to induce mitochondrial dysfunction, and, together with Chromium (VI) as genotoxic based on the increased histone H2AX phosphorylation. Crotonaldehyde was identified as an oxidative stress inducer and Arsenic as a stress kinase pathway activator. This study demonstrates that a combination of impedance-based and HCS technologies provides a robust tool for in vitro assessment of CS constituents.
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PMID:High Content Screening Analysis to Evaluate the Toxicological Effects of Harmful and Potentially Harmful Constituents (HPHC). 2722 13