| N-methyl-N'-nitro-N-nitrosoguanidine activates multiple cell death mechanisms in human fibroblasts. | |
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MedLine Citation:
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PMID: 17678437 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Response to genotoxic stress may trigger the activation of distinct mechanisms that serve to promote cell death, including apoptosis and necrosis. In this study we examined the response of human fibroblasts, either proficient or deficient for the damage-activated protein kinase ataxia telangiectasia-mutated (ATM), to the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Analysis of both long- and short-term viability shows that both ATM-proficient YZ-5 and ATM-deficient EBS-7 fibroblasts display a cytotoxic response to MNNG. Consistent with activation of apoptosis in response to MNNG, we observed increased caspase-3 cleavage and activity, appearance of fragmented nuclei, and increased staining with annexin V in both ATM-proficient and -deficient fibroblasts. Flow cytometry demonstrated that these cell lines also display a nonapoptotic cell death in response to MNNG. This form of cell death is associated with activation of poly-ADP ribose polymerase (PARP), and analysis of PARP activity indicated increased protein poly(ADP-ribosylation) in YZ-5 when compared to EBS-7. This PARP activity was accompanied by apoptosis-inducing factor release and translocation from the mitochondria to the nucleus. Finally, the PARP inhibitor 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone (DPQ) or the caspase-3 inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone dramatically diminished the cytotoxic response to MNNG, reinforcing the roles for apoptotic and nonapoptotic cell death in human fibroblasts treated with MNNG. From these findings, we conclude that MNNG induces a heterogeneous death response in human fibroblasts. |
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Authors:
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Michael W Lee; Wan-Ju Kim; Dillon I Beardsley; Kevin D Brown |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: DNA and cell biology Volume: 26 ISSN: 1044-5498 ISO Abbreviation: DNA Cell Biol. Publication Date: 2007 Sep |
Date Detail:
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Created Date: 2007-09-21 Completed Date: 2007-10-23 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 9004522 Medline TA: DNA Cell Biol Country: United States |
Other Details:
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Languages: eng Pagination: 683-94 Citation Subset: IM |
Affiliation:
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Department of Biochemistry and Molecular Biology and the UF-Shands Cancer Center Program in Cancer Genetics, Epigenetics and Tumor Virology, University of Florida College of Medicine, Gainesville, Florida 32610, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Annexin A5
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metabolism Caspases / metabolism Cell Cycle Proteins / genetics, physiology* Cell Death / drug effects Cell Nucleus / metabolism Cells, Cultured Chromatin / metabolism Colony-Forming Units Assay DNA-Binding Proteins / genetics, physiology* Enzyme Inhibitors / pharmacology Fibroblasts / drug effects*, metabolism Humans Immunoblotting Methylnitronitrosoguanidine / pharmacology* Poly(ADP-ribose) Polymerases / metabolism Protein Transport Protein-Serine-Threonine Kinases / genetics, physiology* Tumor Suppressor Proteins / genetics, physiology* |
| Grant Support | |
ID/Acronym/Agency:
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R01-CA102289/CA/NCI NIH HHS; T32-CA09126/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Annexin A5; 0/Cell Cycle Proteins; 0/Chromatin; 0/DNA-Binding Proteins; 0/Enzyme Inhibitors; 0/Tumor Suppressor Proteins; 70-25-7/Methylnitronitrosoguanidine; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/ataxia telangiectasia mutated protein; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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