Inhibition of apoptosis by Nur77 through NF-κB activity modulation

Abstract

The orphan nuclear receptor Nur77 has been described as a mediator of apoptosis and has also been associated with growth promotion and apoptotic resistance. This study aimed at evaluating the contribution of Nur77 to different apoptotic stimuli. Nur77 overexpression in the fibroblastic cell line HEK293 promoted resistance to programmed cell death induced by death receptor engagement, DNA-damaging agents and endoplasmic reticulum stress. Nur77 overexpression led to enhanced NF-jB activity, and DNA-binding inhibitors confirmed the contribution of NF-jB to Nur77 antiapoptotic activity. Nur77 overexpression leads to NF-jBdependent induction of the antiapoptotic gene cIAP1. Paradoxically, while dominant-negative Nur77 expression sensitised cells to Fas ligand-induced cell death, it protected cells from endoplasmic reticulum stress apoptosis in a manner similar to wild-type Nur77. These results show that nuclear crosstalk between Nur77 and other transcription factors contribute to cell fate in response to different apoptosis-inducing agents.

Perturbation of Transcription Factor Nur77 Expression Mediated by Myocyte Enhancer Factor 2D (MEF2D) Regulates Dopaminergic Neuron Loss in Response to 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

“…These results are consistent with other reports indicating a role for Nur77 in survival, as seen in TNF␣ (23) and ceramideinduced cell death (22), and Nur77-NFB inhibition of apoptosis (54). However, the role of Nur77 appears context dependent.…”

NGFI-B Nuclear Orphan Receptor Nurr1 Interacts with p53 and Suppresses Its Transcriptional Activity

“…For example, Nur77 survives cells in tumor necrosis factor-induced cell death (21) and prevents A20B cells from ceramide-induced cell death (22). It is most likely that Nur77 exerts its antiapoptotic effects by functioning in the nucleus (21,23).…”

Human T-Cell Leukemia Virus Type 1 Tax Enhances Serum Response Factor DNA Binding and Alters Site Selection

“…Nur77 is an SRF-responsive immediate-early gene that has been implicated in regulation of apoptosis and cellular proliferation (33). Recently, Nur77 has been reported to play a role in resistance to apoptosis in the presence of increased NF-B activity (17). This is a very intriguing observation, since Tax also activates NF-B-dependent transcription and Tax-expressing cells have been shown to be resistant to apoptosis (10,15,29,39,56).…”