c-Rel is required for the protection of B cells from antigen receptor-mediated, but not Fas-mediated, apoptosis.
The NF-kappaB/Rel transcription factor family has been shown to protect many cell types from apoptotic signals. However, it is not known whether NF-kappaB is required for all survival pathways and whether each NF-kappaB member plays a unique or a redundant role. Here we describe the results of studies on the role of c-Rel in survival. Mature B cells from c-Rel(-/-) mice exhibit defects in survival, including sensitivity to Ag receptor-mediated apoptosis as well as increased sensitivity to ionizing radiation and glucocorticoids. Transgene expression of Bcl-x(L), a c-Rel target gene, rescues c-Rel(-/-) B cells from their survival defects. Thus, c-Rel-dependent survival pathways are crucial for protection from apoptotic signals that target the mitochondrial pathway. Despite a lack of Bcl-x(L), c-Rel(-/-) B cells can still be rescued from Fas-mediated apoptosis via B cell receptor signaling. The Fas apoptosis inhibitor molecule and FLICE inhibitory protein (c-FLIP) proteins are up-regulated normally in c-Rel(-/-) B cells, and these two molecules may play a more physiological role in the Fas pathway. Furthermore, unlike the TNF sensitivity of RelA(-/-) fibroblasts, c-Rel-deficient fibroblasts are refractory to TNF-mediated cell death. Thus, c-Rel is dispensable for protection against death receptor-mediated apoptosis. Taken together, our data suggest that distinct NF-kappaB/Rel members are required for protecting cells from different types of apoptotic signals.
Owyang
A M
AM
Division of Immunology, Department of Medicine, Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10021, USA.
Tumang
J R
JR
Schram
B R
BR
Hsia
C Y
CY
Behrens
T W
TW
Rothstein
T L
TL
Liou
H C
HC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins; D001402:B-Lymphocytes / Q000502:physiology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000502:physiology; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D005720:Gamma Rays; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D020569:Proto-Oncogene Proteins c-rel / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051020:bcl-X Protein; D019014:fas Receptor / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; C494812:Bcl2l1 protein, mouse; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; C506387:Cflar protein, mouse; C498892:Faim protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D020569:Proto-Oncogene Proteins c-rel; D011948:Receptors, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D019014:fas Receptor; D003907:Dexamethasone