Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis.
The induction of programmed cell death, or apoptosis, involves activation of a signalling system, many elements of which remain unknown. The sphingomyelin pathway, initiated by hydrolysis of the phospholipid sphingomyelin in the cell membrane to generate the second messenger ceramide, is thought to mediate apoptosis in response to tumour-necrosis factor (TNF)-alpha, to Fas ligand and to X-rays. It is not known whether it plays a role in the stimulation of other forms of stress-induced apoptosis. Given that environmental stresses also stimulate a stress-activated protein kinase (SAPK/JNK), the sphingomyelin and SAPK/JNK signalling systems may be coordinated in induction of apoptosis. Here we report that ceramide initiates apoptosis through the SAPK cascade and provide evidence for a signalling mechanism that integrates cytokine- and stress-activated apoptosis.
Verheij
M
M
Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York 10021, USA.
Bose
R
R
Lin
X H
XH
Yao
B
B
Jarvis
W D
WD
Grant
S
S
Birrer
M J
MJ
Szabo
E
E
Zon
L I
LI
Kyriakis
J M
JM
Haimovitz-Friedman
A
A
Fuks
Z
Z
Kolesnick
R N
RN
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D002417:Cattle; D002460:Cell Line; D002518:Ceramides / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048056:Mitogen-Activated Protein Kinase 9; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D002518:Ceramides; C064769:N-acetylsphingosine; D016755:Proto-Oncogene Proteins c-jun; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; D048056:Mitogen-Activated Protein Kinase 9; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D013110:Sphingosine