Early lethality, functional NF-kappaB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice.
TRAF2 is an intracellular signal-transducing protein recruited to the TNFR1 and TNFR2 receptors following TNF stimulation. To investigate the physiological role of TRAF2, we generated TRAF2-deficient mice. traf2-/- mice appeared normal at birth but became progressively runted and died prematurely. Atrophy of the thymus and spleen and depletion of B cell precursors also were observed. Thymocytes and other hematopoietic progenitors were highly sensitive to TNF-induced cell death and serum TNF levels were elevated in these TRAF2-deficient animals. Examination of traf2-/- cells revealed a severe reduction in TNF-mediated JNK/SAPK activation but a mild effect on NF-kappaB activation. These results suggest that TRAF2-independent pathways of NF-kappaB activation exist and that TRAF2 is required for an NF-kappaB-independent signal that protects against TNF-induced apoptosis.
Yeh
W C
WC
Amgen Institute, Department of Medical Biophysics, University of Toronto, Ontario, Canada.
Shahinian
A
A
Speiser
D
D
Kraunus
J
J
Billia
F
F
Wakeham
A
A
de la Pompa
J L
JL
Ferrick
D
D
Hum
B
B
Iscove
N
N
Ohashi
P
P
Rothe
M
M
Goeddel
D V
DV
Mak
T W
TW
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D003513:Cycloheximide / Q000494:pharmacology; D004789:Enzyme Activation; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology; D048031:JNK Mitogen-Activated Protein Kinases; D008099:Liver / Q000196:embryology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000502:physiology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016328:NF-kappa B; D011500:Protein Synthesis Inhibitors; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases