Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.5.1.2 (DNA ligase)
 2,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arsenic is a human carcinogen whose mechanism of action is unknown. Previously, this laboratory demonstrated that arsenite acts as a comutagen by interfering with DNA repair, although a specific DNA repair enzyme sensitive to arsenite has not been identified. A number of stable arsenite-sensitive and arsenite-resistant sublines of Chinese hamster V79 cells have now been isolated. In order to gain understanding of possible targets for arsenite's action, one arsenite-resistant subline, As/R28A, was chosen as a donor for a cDNA expression library. The library from arsenite-induced As/R28A cells was transfected into arsenite-sensitive As/S5 cells, and transfectants were selected for arsenite-resistance. Two cDNAs, asr1 and asr2, which confer arsenite resistance to arsenite-hypersensitive As/S5 cells as well as to wild-type cells, were isolated. asr1 shows almost complete homology with the rat fau gene, a tumor suppressor gene which contains a ubiquitin-like region fused to S30 ribosomal protein. Arsenite was previously shown to inhibit ubiquitin-dependent proteolysis. These results suggest that the tumor suppressor fau gene product or some other aspect of the ubiquitin system may be a target for arsenic toxicity and that disruption of the ubiquitin system may contribute to the genotoxicity and carcinogenicity of arsenite.
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PMID:Expression cloning for arsenite-resistance resulted in isolation of tumor-suppressor fau cDNA: possible involvement of the ubiquitin system in arsenic carcinogenesis. 1006 70

Arsenic compounds have recently been shown to induce high rates of complete remission in patients with acute promyelocytic leukemia (APL). One of these compounds, As(2)O(3), induces apoptosis in APL cells via a mechanism independent of the retinoic acid pathway. To test the hypothesis that arsenic compounds may be effective against other forms of acute myelogenous leukemia (AML), we studied the membrane-permeable arsenic compound phenylarsine oxide (PAO). Because interleukin-1beta (IL-1beta) plays a key role in AML cell proliferation, we first tested the effect of PAO on OCIM2 and OCI/AML3 AML cell lines, both of which produce IL-1beta and proliferate in response to it. We found that PAO inhibited the proliferation of both OCIM2 and OCI/AML3 cells in a dose-dependent fashion (0.01 to 0.1 micromol/L) and that IL-1beta partially reversed this inhibitory effect. We then measured IL-1beta levels in these cells by using an enzyme-linked immunosorbent assay and Western immunoblotting and found that PAO almost completely abolished the production of IL-1beta in these AML cells, whereas it did not affect the production of IL-1 receptor antagonist. Because PAO inhibits activation of the transcription factor NF-kappaB and because NF-kappaB modulates an array of signals controlling cellular survival, proliferation, and cytokine production, we also studied the effect of PAO on NF-kappaB activation in AML cells and found that PAO suppressed the IL-1beta-induced activation of NF-kappaB. Because inhibition of NF-kappaB may result in cellular apoptosis, we also tested whether PAO may induce apoptotic cell death in AML cells. We found that PAO induced apoptosis in OCIM2 cells through activation of the cystein protease caspase 3 and subsequent cleavage of its substrate, the DNA repair enzyme poly (ADP-ribose) polymerase. The PAO-induced apoptosis was caspase dependent, because it was completely blocked by the caspase inhibitor Z-DEVD-FMK. Finally, we tested the effect of PAO on fresh AML marrow cells from 7 patients with newly diagnosed AML and found that PAO suppressed AML colony-forming cell proliferation in a dose-dependent fashion. Taken together, our data showing that PAO is an effective in vitro inhibitor of AML cells suggest that this compound may have a role in future therapies for AML.
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PMID:Phenylarsine oxide blocks interleukin-1beta-induced activation of the nuclear transcription factor NF-kappaB, inhibits proliferation, and induces apoptosis of acute myelogenous leukemia cells. 1051 88

The groundwater arsenicals have brought dreadful misery for the people residing in the endemic regions of West Bengal, India. Arsenic-related anomalies include arsenicosis, hyperkera-tosis, gastric complications, liver fibrosis, peripheral neuropathy, and cancer. Some of these diseases have been frequently associated with overproduction of reactive oxygen species that cause DNA damage and improper functioning of body's antioxidant defense mechanism. Natural polyphenols present in tea serve as excellent antioxidants. In the present study, an attempt has been made to elucidate the role of representative polyphenols and extracts of green and black tea in modulating sodium arsenite (As III)-induced DNA damage in normal human lymphocytes. Comet assay was used to detect the DNA damage. Arsenic-induced oxidative stress was measured with generation of reactive oxygen species, lipid peroxidation, and activity of some antioxidant enzymes. Expression of some repair enzymes such as poly(ADP-ribose) polymerase and DNA polymerase beta was measured to assess the effect of tea on DNA repair. Tea afforded efficient reduction of As III-induced DNA damage in human lymphocytes. Tea also quenched the excessive production of reactive oxygen species by arsenic, reduced the elevated levels of lipid peroxidation, and increased the activity of antioxidant enzymes such as catalase, superoxide dismutase, and glutathione peroxidase. Furthermore, tea enhanced recovery of DNA damage, which was indicative of repair as confirmed by unscheduled DNA synthesis and pronounced expression of DNA repair enzyme poly(ADP-ribose) polymerase. It is speculated that the antioxidant potential and repair-inducing capacity of tea might help in combating the severe genotoxic effects induced by arsenic in the human population.
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PMID:In vitro mitigation of arsenic toxicity by tea polyphenols in human lymphocytes. 1819 36