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Nur77 as a survival factor in tumor necrosis factor signaling
Shinobu Suzuki1, Nobutaka Suzuki, Christine Mirtsos
1Advanced Medical Discovery Institute, University Health Network and Department of Medical Biophysics, University of Toronto, 620 University Avenue, Suite 706, Toronto, ON, Canada M5G 2C1.
Abstract:
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.
Insights
The immediate-early gene Nur77 (nuclear receptor subfamily 4 group A member 1) antagonizes apoptosis in tumor necrosis factor (TNF) signaling. Nur77 acts as a survival protein, protecting cells from TNF-induced death.
Area of Science:
- Cellular biology
- Molecular biology
- Immunology
Background:
- Immediate-early genes like Nur77 are rapidly induced by stress stimuli such as tumor necrosis factor (TNF).
- Nur77 has been previously linked to mediating apoptosis in T cells and tumor cells.
- The role of Nur77 in TNF-induced apoptosis remains incompletely understood.
Purpose of the Study:
- To investigate the role of Nur77 in TNF-mediated apoptosis.
- To determine the signaling pathways involved in Nur77 induction by TNF.
- To elucidate the cellular localization and function of Nur77 during TNF signaling.
Main Methods:
- Utilized gene expression analysis to study Nur77 induction by TNF.
- Employed ectopic expression and dominant-negative constructs to assess Nur77 function.
- Examined cellular localization of Nur77 in response to TNF using mouse embryonic fibroblasts.
- Investigated the involvement of NF-kappa B and TRAF2 signaling pathways.
Main Results:
- Nur77 expression is strongly induced by TNF, largely independent of NF-kappa B.
- Ectopic Nur77 expression protects various cell types (wild-type, TRAF2-/-, RelA-/-) from TNF-induced apoptosis.
- Dominant-negative Nur77 accelerates TNF-mediated cell death.
- In response to TNF, Nur77 localizes to the nucleus, not the mitochondria, in mouse embryonic fibroblasts.
Conclusions:
- Nur77 functions as a survival effector protein in TNF-mediated signaling.
- The anti-apoptotic role of Nur77 in TNF signaling is independent of its mitochondrial localization.
- Nur77 represents a novel target for modulating cell survival in TNF-related pathways.