Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death.
Through its type 1 receptor (TNFR1), the cytokine TNF elicits an unusually wide range of biological responses, including inflammation, tumor necrosis, cell proliferation, differentiation, and apoptosis. We investigated how TNFR1 activates different effector functions; the protein kinase JNK, transcription factor NF-kappaB, and apoptosis. We found that the three responses are mediated through separate pathways. Recruitment of the signal transducer FADD to the TNFR1 complex mediates apoptosis but not NF-kappaB or JNK activation. Two other signal transducers, RIP and TRAF2, mediate both JNK and NF-kappaB activation. These two responses, however, diverge downstream to TRAF2. Most importantly, JNK activation is not involved in induction of apoptosis, while activation of NF-kappaB protects against TNF-induced apoptosis.
Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla 92093-0636, USA.
Z G
ZG
Liu
H
H
Hsu
D V
DV
Goeddel
M
M
Karin
D000230:Adenocarcinoma / Q000473:pathology; D015703:Antigens, CD / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D029681:Arabidopsis Proteins; D001943:Breast Neoplasms / Q000473:pathology; D004789:Enzyme Activation; D044943:Fatty Acid Desaturases / Q000502:physiology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D016328:NF-kappa B / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology; D010766:Phosphorylation; D010940:Plant Proteins / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D015703:Antigens, CD; D029681:Arabidopsis Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D010940:Plant Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis; D011494:Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases