Document Detail

SBDS-deficiency results in deregulation of reactive oxygen species leading to increased cell death and decreased cell growth.
MedLine Citation:
PMID:  20979173     Owner:  NLM     Status:  In-Process    
BACKGROUND: Shwachman-Diamond syndrome (SDS) is characterized by reduced hematopoietic and exocrine pancreatic cell numbers and a marked propensity for leukemia. Most patients have mutations in the SBDS gene. We previously reported that SBDS-deficient cells overexpress Fas, undergo accelerated spontaneous and Fas-mediated apoptosis and grow slowly. However the mechanism of how SBDS regulates apoptosis remains unknown. Several studies have shown that reactive oxygen species (ROS) regulate cell growth and spontaneous and Fas-mediated cell death. Therefore, we hypothesized that SBDS-deficiency disrupts ROS regulation and subsequently increases sensitivity to Fas stimulation and reduced cell growth. PROCEDURE: SBDS was knocked down in HeLa cervical cancer cells and TF-1 myeloid cells using short hairpin RNA. ROS levels were evaluated by oxidation of 2',7'-dichlorodihydrofluorescein diacetate. Apoptosis and cell growth were evaluated with and without antioxidants by annexin V/propidium iodide and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, respectively. RESULTS: We found that shRNA mediated SBDS-knockdown resulted in a significant increase in ROS levels compared to control cells. Fas stimulation further increased ROS levels in the SBDS-knockdown HeLa cells more than in the controls. Importantly, balancing ROS levels by antioxidants rescued SBDS-deficient cells from spontaneous and Fas-mediated apoptosis and reduced cell growth. CONCLUSIONS: ROS levels are increased in SBDS-deficient cells, which leads to increased apoptosis and decreased cell growth. Increased baseline and Fas-mediated ROS levels in SBDS-deficient cells can enhance the sensitivity to Fas stimulation. By balancing ROS levels, antioxidants can improve cell growth and survival in SBDS-deficient cells.
Chhaya Ambekar; Bikul Das; Herman Yeger; Yigal Dror
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Pediatric blood & cancer     Volume:  55     ISSN:  1545-5017     ISO Abbreviation:  Pediatr Blood Cancer     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-10-27     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101186624     Medline TA:  Pediatr Blood Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1138-44     Citation Subset:  IM    
Cell Biology Program, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
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MeSH Terms
Grant Support
HPA161281//Canadian Institutes of Health Research

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