REQUIREMENT FOR GD3 GANGLIOSIDE IN CD95- AND CERAMIDE-INDUCED APOPTOSIS

Gangliosides participate in development and tissue differentiation, Cr oss-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 de pended on integral receptor ''death domains'' and on activation of a f amily of cysteine proteases called caspases. Cell-permeating ceramides , which are potent inducers of apoptosis, also triggered GD3 synthesis , GD3 disrupted mitochondrial transmembrane potential (Delta psi(m),), and induced apoptosis, in a caspase-independent fashion. Transient ov erexpression of the GD3 synthase gene directly triggered apoptosis, Ph armacological inhibition of GD3 synthesis and exposure to GD3 synthase antisense oligodeoxynucleotides prevented CD95-induced apoptosis. Thu s, GD3 ganglioside mediates the propagation of CD95-generated apoptoti c signals in hematopoietic cells.