Characteristics of Nur77 and its ligands as potential anticancer compounds (Review)

Abstract

Nuclear receptor subfamily 4 group A member 1 (NR4A1; also termed Nur77/TR3/NGFIB), a member of the nuclear receptor superfamily, is expressed as an early response gene to regulate the expression of multiple target genes. Nur77 has the typical structure of a nuclear receptor, including an N-terminal domain, a DNA binding domain, and a ligand-binding domain. The expression and localization of Nur77 are closely associated with its roles in cell proliferation and apoptosis. Nur77 was first identified as an orphan receptor, the endogenous ligand of which has not yet been identified; however, an increasing number of compounds targeting Nur77 have been reported to have beneficial effects in the treatment of cancer and other diseases. This review provides a brief overview of the identification, structure, expression and localization, transcriptional role and non-genomic function of Nur77, and summarizes the ligands that have been shown to interact with Nur77, including cytosporone B, cisplatin, TMPA, PDNPA, CCE9, THPN, Z-ligustilide, celastrol and bisindole methane compounds, which may potentially be used to treat cancer in humans.

A Regulation Loop between YAP and NR4A1 Balances Cell Proliferation and Apoptosis

“…NR4A1 (also called Nur77, TR3, or NGFIB) is an orphan nuclear receptor that belongs to the steroid/thyroid/retinoid receptor superfamily (Hazel et al, 1988). NR4A1 contains DNA binding domain (DBD) and ligand binding domain (LBD) (Lin et al, 2004), by which NR4A1 is activated and regulates gene expression (Wu and Chen, 2018). In addition, it plays a significant role in pro-apoptotic function through mitochondrial localization and binding to Bcl-2 (Godoi et al, 2016;Lin et al, 2004).…”

Glycation of Apolipoprotein A-IV Impairs Angiogenesis Through The Orphan Nuclear Receptor Nur77

“…And we found a new target protein Nur77, who play an important role in G-apo A-induced antiangiogenesis. Nur77(NR4A1) is one of the NR4A subfamily, which consists of 3 well conserved members, Nur77, Nurr1 (NR4A2) and NOR-1 (NR4A3), respective [35]. NR4A receptors are immediate-early genes that are regulated by many physiological stimuli including growth factors, hormones, and in ammatory signals and are involved in a wide array of important biological process, including cell apoptosis, brain development, glucose metabolism, and vascular remodeling [36].…”

Cancer Treatment Goes Viral: Using Viral Proteins to Induce Tumour-Specific Cell Death

“…In normal conditions Nur77 is found in the nucleus but regulated by phosphorylation, which occurs by MAPK and AKT. Phosphorylation of Nur77 drives the abnormal translocation of the transcription factor to the mitochondria where it causes MOMP ensuing cytochrome c release [110]. The activity of this transcription factor in the context of viral protein cancer toxicity has been mostly studied in CAV-Apoptin.…”

“…Interestingly, Nur77 is known to interact with Bcl-2 and turn it from anti-to pro-apoptotic which may explain the conflicting results for this protein [111]. Nur77 is also important for HGV-Apoptin as treatment triggers cytoplasmic translocation of Nur77 93 Nevertheless, although less is known about this transcription factor in other viral protein mechanisms, studies have found that Nur77 interacts with an E1A binding partner p300, and the overexpression of E1A can repress Nur77 transactivation [110,112].…”