Requirement for GD3 ganglioside in CD95- and ceramide-induced apoptosis.
Gangliosides participate in development and tissue differentiation. Cross-linking of the apoptosis-inducing CD95 protein (also called Fas or APO-1) in lymphoid and myeloid tumor cells triggered GD3 ganglioside synthesis and transient accumulation. CD95-induced GD3 accumulation depended on integral receptor "death domains" and on activation of a family of cysteine proteases called caspases. Cell-permeating ceramides, which are potent inducers of apoptosis, also triggered GD3 synthesis. GD3 disrupted mitochondrial transmembrane potential (DeltaPsim), and induced apoptosis, in a caspase-independent fashion. Transient overexpression of the GD3 synthase gene directly triggered apoptosis. Pharmacological inhibition of GD3 synthesis and exposure to GD3 synthase antisense oligodeoxynucleotides prevented CD95-induced apoptosis. Thus, GD3 ganglioside mediates the propagation of CD95-generated apoptotic signals in hematopoietic cells.
De Maria
R
R
Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata," 00133 Rome, Italy.
Lenti
L
L
Malisan
F
F
d'Agostino
F
F
Tomassini
B
B
Zeuner
A
A
Rippo
M R
MR
Testi
R
R
D017209:Apoptosis; D002518:Ceramides / Q000494:pharmacology / Q000502:physiology*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005732:Gangliosides / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials; D008928:Mitochondria / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism / Q000502:physiology*
D002518:Ceramides; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D005732:Gangliosides; D009025:Morpholines; D016376:Oligonucleotides, Antisense; D019014:fas Receptor; C026226:ganglioside, GD3; C033110:RV 538; D012799:Sialyltransferases; C043662:alpha-N-acetylneuraminate alpha-2,8-sialyltransferase; D003546:Cysteine Endopeptidases