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Cell autonomous apoptosis defects in acid sphingomyelinase knockout fibroblasts
J Lozano1, S Menendez, A Morales
1Laboratory of Signal Transduction and Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
The Journal of Biological Chemistry
|October 14, 2000
Summary
Stress-induced ceramide generation initiates apoptosis. Acid sphingomyelinase (ASMase)-deficient cells resist apoptosis, but ceramide administration restores sensitivity, proving ceramide
Area of Science:
- Cell Biology
- Biochemistry
- Genetics
Background:
- Evidence suggests stress-induced sphingomyelin hydrolysis to ceramide triggers apoptosis.
- Previous models using Niemann-Pick disease lymphoblasts or ASMase-deficient mice had limitations.
Purpose of the Study:
- To investigate the role of acid sphingomyelinase (ASMase) in stress-induced apoptosis using a novel mouse model.
- To determine if ceramide deficiency, rather than ASMase deficiency itself, dictates apoptosis sensitivity.
Main Methods:
- Utilized ASMase-deficient mouse embryonic fibroblasts (MEFs).
- Exposed MEFs to various apoptotic stressors including radiation, staurosporine, TNF-α/actinomycin D, and serum withdrawal.
- Administered exogenous natural ceramide to rescue the apoptotic phenotype.
Main Results:
- ASMase-deficient MEFs exhibited defects in apoptosis, specifically resistance to radiation-induced cell death.
- This resistance was stress-type specific and not global.
- Supplementation with natural ceramide successfully restored apoptosis sensitivity in ASMase-deficient MEFs.
Conclusions:
- Ceramide is obligate for apoptosis induction in response to specific stresses.
- Apoptosis resistance in ASMase-deficient cells is due to ceramide deficiency, not the absence of the enzyme itself.
- Restoring ceramide levels can overcome the apoptotic defect, validating ceramide's critical role.