The death domain kinase RIP mediates the TNF-induced NF-kappaB signal.
The death domain serine/threonine kinase RIP interacts with the death receptors Fas and tumor necrosis receptor 1 (TNFR1). In vitro, RIP stimulates apoptosis, SAPK/JNK, and NF-kappaB activation. To define the physiologic role(s) that RIP plays in regulating apoptosis in vivo, we introduced a rip null mutation in mice through homologous recombination. RIP-deficient mice appear normal at birth but fail to thrive, displaying extensive apoptosis in both the lymphoid and adipose tissue and dying at 1-3 days of age. In contrast to a normal thymic anti-Fas response, rip-/- cells are highly sensitive to TNFalpha-induced cell death. Sensitivity to TNFalpha-mediated cell death in rip-/- cells is accompanied by a failure to activate the transcription factor NF-kappaB.
Kelliher
M A
MA
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. kelliher@rascal.med.harvard.edu
Grimm
S
S
Ishida
Y
Y
Kuo
F
F
Stanger
B Z
BZ
Leder
P
P
D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D016207:Cytokines; D005183:Failure to Thrive; D005804:Genes, Lethal; D048031:JNK Mitogen-Activated Protein Kinases; D008221:Lymphoid Tissue / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D019014:fas Receptor
D016207:Cytokines; D016328:NF-kappa B; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D017346:Protein Serine-Threonine Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases