Fas- or ceramide-induced apoptosis is mediated by a Rac1-regulated activation of Jun N-terminal kinase/p38 kinases and GADD153.
In the present study, we show that Fas receptor ligation or cellular treatment with synthetic C6-ceramide results in activation or phosphorylation, respectively, of the small G-protein Rac1, Jun N-terminal kinase (JNK)/p38 kinases (p38-K), and the transcription factor GADD153. A signaling cascade from the Fas receptor via ceramide, Ras, Rac1, and JNK/p38-K to GADD153 is demonstrated employing transfection of transdominant inhibitory N17Ras, N17Rac1, c-Jun, or treatment with a specific p38-K inhibitor. The critical function of this signaling cascade is indicated by prevention of Fas- or C6-ceramide-induced apoptosis after inhibition of Ras, Rac1, or JNK/p38-K.
Brenner
B
B
Department of Pediatrics, University of Heidelberg, INF 150, 69120 Heidelberg, Germany.
Koppenhoefer
U
U
Weinstock
C
C
Linderkamp
O
O
Lang
F
F
Gulbins
E
E
D000954:Antigens, Surface / Q000378:metabolism; D017209:Apoptosis; D022762:CCAAT-Enhancer-Binding Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002518:Ceramides / Q000494:pharmacology*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D053222:Fas Ligand Protein; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D019014:fas Receptor / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins
D000954:Antigens, Surface; D022762:CCAAT-Enhancer-Binding Proteins; D002518:Ceramides; C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D008562:Membrane Glycoproteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D019014:fas Receptor; D051742:Transcription Factor CHOP; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins