Death-associated protein (DAP) kinase plays a central role in ceramide-induced apoptosis in cultured hippocampal neurons.
Treatment of cultured hippocampal neurons with high concentrations of short-chain acyl ceramide derivatives, such as N-hexanoyl-D-sphingosine (C(6)-Cer), results in apoptotic cell death. We now show that death-associated protein (DAP) kinase plays an important role in mediating this effect. Upon incubation with C(6)-Cer, DAP kinase levels are elevated as early as 1 h after treatment, reaching levels 2-3-fold higher than untreated cells after 4 h. Neurons cultured from DAP kinase-deficient mice were significantly less sensitive to apoptosis induced by C(6)-Cer or by ceramide generated by high concentrations of nerve growth factor. A peptide corresponding to the 17 amino acids at the C terminus of DAP kinase protected wild type neurons from C(6)-Cer-induced death and from death induced by the addition of exogenous bacterial neutral sphingomyelinase, whereas a scrambled peptide had no protective effect, implying that the DAP kinase C-terminal tail inhibits the function of DAP kinase. Together, these data demonstrate that DAP kinase plays a central role in ceramide-induced cell death in neurons, but the pathway in which DAP kinase is involved is not the only one via which ceramide can induce apoptosis.
Pelled
Dori
D
Department of Biological Chemistry, Department of Molecular Genetics, and Department of Organic Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
Raveh
Tal
T
Riebeling
Christian
C
Fridkin
Mati
M
Berissi
Hanna
H
Futerman
Anthony H
AH
Kimchi
Adi
A
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D002518:Ceramides / Q000502:physiology*; D064550:Death-Associated Protein Kinases; D006624:Hippocampus / Q000166:cytology*; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology*; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; D002518:Ceramides; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases