While ceramide has emerged as a potent signal transducer, inconsistenc
ies in the kinetics of ceramide generation, or its absence, in respons
e to stimuli have led to confusion and skepticism as to its potential
role in apoptosis or proliferation. Here we show that in U937 and HL60
myeloid leukemia cells and in normal skin fibroblasts, cell-permeant
ceramides can trigger neutral sphingomyelinase activation, sphingomyel
in hydrolysis, and endogenous ceramide generation regardless of Bc12 o
verexpression, These observations identify neutral sphingomyelinase as
a novel target for ceramide and show that this positive feedback mech
anism is responsible for signal propagation, as exemplified by mitogen
-activated protein kinase activation in daunorubicin-treated cells. Th
is study provides insight into a fundamental process of cell biology.
Indeed, such a sustained ceramide-mediated signal throughout the apopt
otic process would ensure self-destruction, perhaps by overriding evol
utionary conserved primal cell survival mechanisms.