title: The death domain kinase RIP mediates the TNF-induced NF-kappaB signal.
abstract: 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.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. kelliher@rascal.med.harvard.edu
authors.forename: M A
authors.initials: MA
authors.lastname: Kelliher
authors.forename: S
authors.initials: S
authors.lastname: Grimm
authors.forename: Y
authors.initials: Y
authors.lastname: Ishida
authors.forename: F
authors.initials: F
authors.lastname: Kuo
authors.forename: B Z
authors.initials: BZ
authors.lastname: Stanger
authors.forename: P
authors.initials: P
authors.lastname: Leder
mesh_terms: 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
chemical_list: 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