Document Detail

Increased susceptibility of spinal muscular atrophy fibroblasts to camptothecin-induced cell death.
MedLine Citation:
PMID:  15862279     Owner:  NLM     Status:  MEDLINE    
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.
Wenlan Wang; Darlise Dimatteo; Vicky L Funanage; Mena Scavina
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Publication Detail:
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:
Title:  Molecular genetics and metabolism     Volume:  85     ISSN:  1096-7192     ISO Abbreviation:  Mol. Genet. Metab.     Publication Date:  2005 May 
Date Detail:
Created Date:  2005-05-02     Completed Date:  2005-09-26     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9805456     Medline TA:  Mol Genet Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  38-45     Citation Subset:  IM    
Nemours Biomedical Research, Alfred I. duPont Hospital for Children, 1600 Rockland Road, Wilmington, DE 19803, USA.
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MeSH Terms
Base Sequence
Camptothecin / toxicity*
Cell Death / drug effects
Cell Survival
Fibroblasts / drug effects,  pathology*
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
1 P20 RR020173-01/RR/NCRR NIH HHS
Reg. No./Substance:
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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