| Increased susceptibility of spinal muscular atrophy fibroblasts to camptothecin-induced cell death. | |
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MedLine Citation:
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PMID: 15862279 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletions or mutations in the telomeric copy of the survival motor neuron (SMN1) gene. Although the SMN protein has been implicated in the biogenesis of ribonucleoprotein complexes and RNA processing, it is not clear how these functions contribute to the pathogenesis of SMA. To gain a further understanding of SMN function, we have investigated its role in cell survival in skin fibroblasts derived from SMA patients and age-matched controls. SMA fibroblasts exposed to camptothecin, a specific inhibitor of DNA topoisomerase I, consistently showed cell death at a lower concentration than normal controls. Treatment with other cell death-inducing agents did not cause differences in survival of SMA fibroblasts as compared with control fibroblasts. Camptothecin treatment resulted in activation of caspase-3 with generation of the caspase-3 cleavage product, poly ADP-ribose polymerase (PARP). Depletion of SMN protein by RNA interference in control fibroblasts increased caspase-3 activity, whereas transfection of SMA fibroblasts with wild-type SMN decreased caspase-3 activity. Our data demonstrate that SMA fibroblasts are more prone to some, but not all, death-stimuli. Vulnerability to death-stimuli is associated with decreased levels of SMN protein and is mediated by activation of caspase-3. |
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Authors:
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Wenlan Wang; Darlise Dimatteo; Vicky L Funanage; Mena Scavina |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. Date: 2005-02-16 |
Journal Detail:
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Title: Molecular genetics and metabolism Volume: 85 ISSN: 1096-7192 ISO Abbreviation: Mol. Genet. Metab. Publication Date: 2005 May |
Date Detail:
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Created Date: 2005-05-02 Completed Date: 2005-09-26 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 9805456 Medline TA: Mol Genet Metab Country: United States |
Other Details:
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Languages: eng Pagination: 38-45 Citation Subset: IM |
Affiliation:
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Nemours Biomedical Research, Alfred I. duPont Hospital for Children, 1600 Rockland Road, Wilmington, DE 19803, USA. wwang@nemours.org |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Atrophy Base Sequence Biopsy Camptothecin / toxicity* Cell Death / drug effects Cell Survival Fibroblasts / drug effects, pathology* Humans Molecular Sequence Data Motor Neurons / pathology Muscular Atrophy, Spinal / genetics, pathology* Nucleic Acid Conformation RNA / chemistry, genetics Sequence Deletion Skin / pathology Telomere / genetics Vitamin K 3 / toxicity |
| Grant Support | |
ID/Acronym/Agency:
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1 P20 RR020173-01/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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58-27-5/Vitamin K 3; 63231-63-0/RNA; 7689-03-4/Camptothecin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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