Cell autonomous apoptosis defects in acid sphingomyelinase knockout fibroblasts

被引:79
作者
Lozano, J
Menendez, S
Morales, A
Ehleiter, D
Liao, WC
Wagman, R
Haimovitz-Friedman, A
Fuks, Z
Kolesnick, R
机构
[1] Mem Sloan Kettering Canc Ctr, Lab Signal Transduct, New York, NY 10021 USA
[2] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10021 USA
关键词
D O I
10.1074/jbc.M006353200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 osmose 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 alpha/ 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 is 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.
引用
收藏
页码:442 / 448
页数:7
相关论文
共 59 条
[1]   Differential effects of glycolipid biosynthesis inhibitors on ceramide-induced cell death in neuroblastoma cells [J].
Bieberich, E ;
Freischütz, B ;
Suzuki, M ;
Yu, RK .
JOURNAL OF NEUROCHEMISTRY, 1999, 72 (03) :1040-1049
[2]   MODULATION OF CELL-GROWTH AND DIFFERENTIATION BY CERAMIDE [J].
BIELAWSKA, A ;
LINARDIC, CM ;
HANNUN, YA .
FEBS LETTERS, 1992, 307 (02) :211-214
[3]   Common regulation of apoptosis signaling induced by CD95 and the DNA-damaging stimuli etoposide and γ-radiation downstream from caspase-8 activation [J].
Boesen-de Cock, JGR ;
Tepper, AD ;
de Vries, E ;
van Blitterswijk, WJ ;
Borst, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (20) :14255-14261
[4]   CD95 (Fas/APO-1) induces ceramide formation and apoptosis in the absence of a functional acid sphingomyelinase [J].
Boesen-de Cock, JGR ;
Tepper, AD ;
de Vries, E ;
van Blitterswijk, WJ ;
Borst, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (13) :7560-7565
[5]   CERAMIDE SYNTHASE MEDIATES DAUNORUBICIN-INDUCED APOPTOSIS - AN ALTERNATIVE MECHANISM FOR GENERATING DEATH SIGNALS [J].
BOSE, R ;
VERHEIJ, M ;
HAIMOVITZFRIEDMAN, A ;
SCOTTO, K ;
FUKS, Z ;
KOLESNICK, R .
CELL, 1995, 82 (03) :405-414
[6]   Ceramide generation by the reaper protein is not blocked by the caspase inhibitor, p35 [J].
Bose, R ;
Chen, P ;
Loconti, A ;
Grüllich, C ;
Abrams, JM ;
Kolesnick, RN .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (44) :28852-28859
[7]   Lack of ceramide generation in TF-1 human myeloid leukemic cells resistant to ionizing radiation [J].
Bruno, AP ;
Laurent, G ;
Averbeck, D ;
Demur, C ;
Bonnet, J ;
Bettaïeb, A ;
Levade, T ;
Jaffrézou, JP .
CELL DEATH AND DIFFERENTIATION, 1998, 5 (02) :172-182
[8]  
Chmura SJ, 1997, CANCER RES, V57, P4340
[9]  
Chmura SJ, 1997, CANCER RES, V57, P1270
[10]   MULTIPLE PATHWAYS ORIGINATE AT THE FAS/APO-1 (CD95) RECEPTOR - SEQUENTIAL INVOLVEMENT OF PHOSPHATIDYLCHOLINE-SPECIFIC PHOSPHOLIPASE-C AND ACIDIC SPHINGOMYELINASE IN THE PROPAGATION OF THE APOPTOTIC SIGNAL [J].
CIFONE, MG ;
RONCAIOLI, P ;
DEMARIA, R ;
CAMARDA, G ;
SANTONI, A ;
RUBERTI, G ;
TESTI, R .
EMBO JOURNAL, 1995, 14 (23) :5859-5868