Nur77 as a survival factor in tumor necrosis factor signaling.
The immediate-early gene Nur77, which encodes an orphan nuclear receptor, is rapidly induced by various stress stimuli, including tumor necrosis factor (TNF). Nur77 has been implicated in mediating apoptosis, particularly in T cells and tumor cells. We report here that Nur77 can play a role in antagonizing apoptosis in TNF signaling. Nur77 expression is strongly induced by TNF. Interestingly, unlike most antiapoptotic molecules, this induced expression of Nur77 is largely independent of NF-kappa B. Ectopic expression of Nur77 can protect wild-type, TRAF2-/-, and RelA-/- cells from apoptosis induced by TNF, whereas expression of a dominant-negative form of Nur77 (DN-Nur77) accelerates TNF-mediated cell death in the mutant cells. In mouse embryonic fibroblasts, Nur77 remains in the nucleus in response to TNF and is not translocated to the mitochondria, where it was reported to mediate apoptosis. Our results suggest that Nur77 is a survival effector protein in the context of TNF-mediated signaling.
Suzuki
Shinobu
S
Advanced Medical Discovery Institute, University Health Network and Department of Medical Biophysics, University of Toronto, 620 University Avenue, Suite 706, Toronto, ON, Canada M5G 2C1.
Suzuki
Nobutaka
N
Mirtsos
Christine
C
Horacek
Thomas
T
Lye
Elizabeth
E
Noh
Seo-Kyu
SK
Ho
Alexandra
A
Bouchard
Denis
D
Mak
Tak W
TW
Yeh
Wen-Chen
WC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000172:deficiency / Q000235:genetics; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D020411:Oligonucleotide Array Sequence Analysis; D021381:Protein Transport; D011506:Proteins / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D004268:DNA-Binding Proteins; D016328:NF-kappa B; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins; D047992:TNF Receptor-Associated Factor 2; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases