| Base excision repair proteins are required for integrin-mediated suppression of bleomycin-induced DNA breakage in murine lung endothelial cells. | |
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MedLine Citation:
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PMID: 17202402 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Engagement of integrin cell adhesion receptors suppresses bleomycin (BLM)-induced DNA strand breakage in endothelial cells. Previous investigation of cells from poly(ADP-ribose) polymerase (PARP)-1 knockout mice and with an inhibitor of the enzyme indicated that this facilitator of base excision repair (BER) is required for integrin-mediated suppression of DNA strand breakage. Here, small inhibitory RNA (siRNA) was used to assess the requirement for the BER proteins, DNA ligase III (Lig3) alpha, PARP-1, and X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1), and for the long-patch BER ligase, DNA ligase I (Lig1), in integrin-mediated protection from BLM-induced DNA breakage. Murine lung endothelial cells (MLECs) were transfected with siRNA, treated with anti-beta1 integrin antibody, and then BLM. 3'-OH in DNA and accumulation of phosphorylated histone H2AX (gammaH2AX), which reflects double-strand breakage, were measured. Integrin antibody inhibited the increases in 3'-OH caused by BLM in MLECs transfected with either control or Lig1 siRNA. However, after knockdown of Lig3alpha, PARP-1, or XRCC1, suppression of DNA breakage by integrin antibody was limited. BLM increased gammaH2AX levels, and integrin treatment inhibited this by 57 to 73% in MLECs transfected with control siRNA. Integrin engagement also inhibited increases in gammaH2AX in BLM-treated cells transfected with Lig1 siRNA. In contrast, Lig3alpha, PARP-1, and XRCC1 siRNAs prevented integrin-mediated inhibition of BLM-induced gammaH2AX levels. The results suggest that the BER proteins, Lig3alpha, PARP-1, and XRCC1, are required for integrin-mediated suppression of BLM-induced DNA breakage. |
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Authors:
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Jane L Rose; Kevin C Reeves; Rostislav I Likhotvorik; Dale G Hoyt |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2007-01-03 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 321 ISSN: 0022-3565 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2007 Apr |
Date Detail:
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Created Date: 2007-03-19 Completed Date: 2007-05-14 Revised Date: 2007-12-03 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 318-26 Citation Subset: IM |
Affiliation:
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Division of Pharmacology, Ohio State University College of Pharmacy, 500 West Twelfth Avenue, Columbus, OH 43210, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antimetabolites, Antineoplastic / toxicity* Bleomycin / antagonists & inhibitors*, toxicity* Blotting, Western Cell Survival / drug effects DNA Damage* DNA Ligases / genetics DNA Repair / drug effects* DNA-Binding Proteins / genetics Endothelial Cells / cytology, drug effects, metabolism* Fluorescent Antibody Technique Green Fluorescent Proteins / biosynthesis, genetics Histones / genetics In Situ Nick-End Labeling Integrins / physiology* Lung / cytology, drug effects, metabolism* Mice Poly(ADP-ribose) Polymerases / antagonists & inhibitors, genetics RNA, Small Interfering / pharmacology Reverse Transcriptase Polymerase Chain Reaction |
| Grant Support | |
ID/Acronym/Agency:
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HL68054/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antimetabolites, Antineoplastic; 0/DNA-Binding Proteins; 0/Histones; 0/Integrins; 0/RNA, Small Interfering; 0/X-ray repair cross complementing protein 1; 0/gamma-H2AX protein, mouse; 11056-06-7/Bleomycin; 147336-22-9/Green Fluorescent Proteins; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 2.4.2.30/poly(ADP-ribose)polymerase-1, mouse; EC 6.5.1.-/DNA Ligases; EC 6.5.1.1/DNA ligase (ATP) |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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