Cell autonomous apoptosis defects in acid sphingomyelinase knockout fibroblasts Journal Article
| Authors: | Lozano, J.; Menendez, S.; Morales, A.; Ehleiter, D.; Liao, W. C.; Wagman, R.; Haimovitz-Friedman, A.; Fuks, Z.; Kolesnick, R. |
| Article Title: | Cell autonomous apoptosis defects in acid sphingomyelinase knockout fibroblasts |
| Abstract: | A body of evidence suggests that stress-induced sphingomyelin hydrolysis to the second messenger ceramide initiates apoptosis in some cells. Although studies using lymphoblasts from Niemann-Pick disease patients or acid sphingomyelinase (ASMase)-deficient mice have provided genetic support for this hypothesis, these models have not been universally accepted as definitive. Here, we show that mouse embryonic fibroblasts (MEFs) prepared from asmase mice manifest cell autonomous defects in apoptosis in response to several stresses. In particular, asmase-/- MEFs failed to generate ceramide and were totally resistant to radiation-induced apoptosis but remained sensitive to staurosporine, which did not induce ceramide, asmase-/- MEFs were also partially resistant to tumor necrosis factor al actinomycin D and serum withdrawal. Thus, resistance to apoptosis in asmase-/- MEFs was not global but rather stress type specific. Most importantly, the sensitivity to stress could be restored in the asmase-/- MEFs by administration of natural ceramide. Overcoming apoptosis resistance by natural ceramide is evidence that it its the lack of ceramide, not ASMase, that determines apoptosis sensitivity. The ability to rescue the apoptotic phenotype without reversing the genotype by the product of the enzymatic deficiency provides proof that ceramide is obligate for apoptosis induction in response to some stresses. |
| Keywords: | controlled study; gene deletion; pathogenesis; nonhuman; animal cell; mouse; phenotype; animals; mice; mice, knockout; cells, cultured; apoptosis; embryo; caspase 3; caspases; animalia; tumor necrosis factor alpha; tumor necrosis factor-alpha; dactinomycin; fibroblast; fibroblasts; radiation, ionizing; stress; genetic disorder; hydrolysis; ceramide; ceramides; sphingomyelin phosphodiesterase; radiation tolerance; niemann pick disease; staurosporine; culture media, serum-free; lymphoblast; priority journal; article |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 276 |
| Issue: | 1 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2001-01-05 |
| Start Page: | 442 |
| End Page: | 448 |
| Language: | English |
| DOI: | 10.1074/jbc.M006353200 |
| PUBMED: | 11031259 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 21 May 2015 -- Source: Scopus |
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