Nuclear receptor 4A (NR4A) family – orphans no more

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Highlights

  • NR4A receptors play a critical role in maintaining cellular homeostasis.

  • NR4A receptors also play critical roles in multiple diseases.

  • Ligands for NR4A receptors have been characterized.

  • NR4A ligands have applications for treating multiple diseases and cancer.

Abstract

The orphan nuclear receptors NR4A1, NR4A2 and NR4A3 are immediate early genes induced by multiple stressors, and the NR4A receptors play an important role in maintaining cellular homeostasis and disease. There is increasing evidence for the role of these receptors in metabolic, cardiovascular and neurological functions and also in inflammation and inflammatory diseases and in immune functions and cancer. Despite the similarities of NR4A1, NR4A2 and NR4A3 and their interactions with common cis-genomic elements, they exhibit unique activities and cell-/tissue-specific functions. Although endogenous ligands for NR4A receptors have not been identified, there is increasing evidence that structurally-diverse synthetic molecules can directly interact with the ligand binding domain of NR4A1 and act as agonists or antagonists, and ligands for NR4A2 and NR4A3 have also been identified. Since NR4A receptors are key factors in multiple diseases, there are opportunities for the future development of NR4A ligands for clinical applications in treating multiple health problems including metabolic, neurologic and cardiovascular diseases, other inflammatory conditions, and cancer.

Introduction

The orphan nuclear receptor (NR) family has been characterized as a collection of nuclear receptors which share many structural domain similarities with other NRs; however, their endogenous ligands are unknown [1]. These receptors include NR0B1 (adrenal hypoplasia congenita critical region on chromosome X gene), NR0B2 (small heterodimer partner), NR1D1/2 (Rev-Erbαβ), NR2C1 (testicular receptor 2), NR2C2 (testicular receptor 2), NR2E1 (tailless), NR2E3 (photoreceptor-specific NR [PNR]), NR2F1 chicken ovalbumin upstream promoter transcription factor 1 (COUP-TFI), NR2F2 (COUP-TFII), NR2F6 (verbA-related protein), NR4A1 (Nur77), NR4A2 (Nurr1), NR4A3 (Nor1), and NR6A1 (GCNF).

In contrast to the other NRs, the orphan NR0B1 (DAX-1) and NR0B2 (SHP) receptors do not express a DNA binding domain (DBD) and primarily function as nuclear cofactors that influence gene expression through protein–protein interactions [2], [3], [4]. The three NR4A receptors have significant structural similarities in their ligand binding domains (LBDs) and DNA BDs, whereas their N-terminal (A/B) domains containing activation function 1 (AF1) are highly divergent [5], [6], [7], [8]. NR4A receptors were initially defined as nerve growth factor-induced-β (NGFI-β) receptors that bind as monomers to an NGFI-β response element (NBRE:AAAGGTCA) [8], [9], [10], [11], [12]. NR4A receptors also bind as a homo- or hetero-dimer to a nur-responsive element (NuRE:TGATATTACCTCCAAATGCCA) which has been characterized from the pro-opiomelanocortin gene promoter [13], [14]. Both NR4A1 and NR4A2 can also bind as heterodimers with the retinoid X receptor (RXR) to a DR5 motif [15], [16]. These receptor-DNA interactions are characteristic of all NRs (except NR0B1 and NR0B2) and there is also evidence that NR4A1 regulates gene expression through interactions with the specificity protein 1 (Sp1) transcription factor bound to its cognate GC-rich motif [17], [18], [19]. NR4A1 acts as a cofactor (along with p300) of Sp1, and many other NRs bind Sp1 and are integral cofactors for expression of Sp1-regulated genes [19], [20], [21], [22], [23], [24], [25], [26], [27], [28].

The initial discovery of NR4A receptors was linked to their rapid induction by multiple stimuli in various tissues/cells and organs and these responses play a role in coping with both exogenous and endogenous stressors and the tissue-specific expression and induction of NR4A receptors contributes to their specificity (reviewed in [29], [30]). For example, NR4A receptors are induced by nerve growth factors in neuronal cells and by apoptosis-inducing agents in cancer cell lines [31], [32], [33], [34], [35], [36], [37]. In contrast, extensive studies with NR4A1 demonstrate that this receptor is not only induced by diverse anti-apoptotic agents but is also highly expressed in solid tumors and exhibits pro-oncogenic activity. Over the past decade, several timely and informative reviews on NR4A receptors have been published [29], [30], [38], [39], [40], [41], [42] and therefore this paper will primarily focus on more recent advances in the field.

Section snippets

NR4A1 in cellular homeostasis and diseases

Individual and combined knockouts of NR4A1, NR4A2 and NR4A3 in mice have been described and extensively investigated to demonstrate the function of these receptors in maintaining cellular homeostasis and their role in disease. Thus, contributions of NR4A1 in metabolic disease, inflammation, atherosclerosis and other responses will be discussed in subsequent sub-sections of this review. One of the earliest functions identified for NR4A1 was its induction in T-cell hybridomas or thymocytes

NR4A2 in cellular homeostasis and disease

The nuclear receptor NR4A2 (Nurr1, HZF-3, RNR1, NOT, DHR38) is the second member of the NR4A family and possesses structural motifs and complex patterns of transcriptional activity similar to NR4A1 and NR4A3. The DNA-binding domain of NR4A2 is over 92% homologous to the same domain of NR4A1 (Nur77), conferring similarities both in sequence identity and function between these receptors [129]. Research over the past two decades has demonstrated activities of NR4A2 associated with energy

NR4A3 in cellular homeostasis and disease

The nuclear receptor NR4A3 (Nor1, TEX, MINOR, CHN) is the third member of the NR4A family and shares many of the same characteristics reported for NR4A1 and NR4A2. NR4A3-mediated transactivation and interactions with various cis-elements, except that unlike NR4A1 and NR4A2, NR4A3 does not form a heterodimer with RXR [15], [16]. Although there is some redundancy in the functions of the three NR4A receptors since these receptors are induced as early immediate genes by some of the same stressors

Summary

NR4A1, NR4A2 and NR4A3 are orphan nuclear receptors and immediate early genes induced by multiple stressors. All three receptors bind the same genomic cis-elements; however, their distinct differences in activities are due, in part, to their more unique N- and C-terminal domains that differentially interact with various cofactors and ligands and their tissue-specific expression. Complete and tissue-specific knockout mouse models uniquely distinguish between the different roles for these

Disclosure

There are no conflicts of interest to disclose.

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