NR4A1 (nuclear receptor subfamily 4, group A, member 1)

2013-01-01   Tzu-Min Chan , Shinn-Zong Lin , Tzyy-Wen Chiou , Horng-Jyh Harn 





The NR4A1 gene is located on human chromosome 12 at position 12q13.13. The gene spans from 52416616 to 52453291 (36.7 Kb) on the forward strand (NCBI).


NR4A1 encodes three transcript variants and variant 3 produces two protein isoforms.
Variant 1 mRNA NCBI Reference number: NM_002135.
Variant 2 mRNA NCBI Reference number: NM_173157.
Variant 3 mRNA NCBI Reference number: NM_001202233.


Atlas Image
Schematic diagram of NR4A1 showing its location on chromosome 12, its orientation relative to surrounding genes, and the three key functional domains of the protein.


NR4A1 is a steroid/thyroid hormone-responsive orphan nuclear receptor that contains three key functional domains: a steroid hormone receptor ligand-independent transactivation domain (AF-1), a nuclear hormone receptor zinc finger domain (ZnF_C4) and a hormone receptor ligand-binding domain (HOLI) (Figure). No natural ligand for NR4A1 has yet been identified (Davis and Lau, 1994; Mohan et al., 2012). NR4A1 is thought to play a role in transcriptional regulation through binding of the ZnF_C4 domain to hormone response elements in DNA (Moehren et al., 2004). This domain contains multiple finger-like structures and interacts with several target molecules, including DNA, RNA, proteins, and/or lipid substrates (Laity et al., 2001). The range of interactions implies that the ZnF_C4 domain has multiple functions in different molecular processes. The HOLI domain influences NR4A1 nuclear translocation and its association with DNA (Bledsoe et al., 2004).


NR4A1 has been detected at varying levels in different human tissues, with particularly high levels in the adrenal cortex, lungs, prostate, ovaries, testes, heart, muscle, thyroid, trachea, olfactory bulb and adrenal gland (Su et al., 2004).


NR4A1 is a nuclear hormone receptor that is activated by association with its ligand to move into the nucleus. For example, in response to n-Butylidenephthalide induced cell death signals, NR4A1 translocates into mitochondria to enhance apoptosis (Chen et al., 2008; Liu et al., 2012).


NR4A1 is involved in multiple molecular processes, including signal transmission, transcriptional regulation, mediation of cell growth, induction of apoptosis, and cell cycle control (Lee et al., 2011; McMorrow and Murphy, 2011; Mohan et al., 2012; van Tiel and de Vries, 2012). NR4A1 acts as a hormone receptor and is stimulated by ligand binding to move into the nucleus and associate with DNA to regulate transcription of multiple genes (Wu et al., 2002). NR4A1 is also involved in several complex pathways that mediate cell survival and apoptosis (Li et al., 2006; Lin et al., 2004). Furthermore, NR4A1 dysfunction has been associated with inflammation and carcinogenesis (Choi et al., 2004; Li et al., 2006). In terms of post-translational modifications, NR4A1 is phosphorylated by protein kinase B at Serine 350 and its acetylation is modulated by p300 and HDAC1 (Kang et al., 2010; Pekarsky et al., 2001).

Cell growth/survival
As a steroid/thyroid hormone receptor, NR4A1 acts as a transcription factor, activating several genes involved in cell growth and survival (Bras et al., 2000). The expression of NR4A1 can be induced by tumor necrosis factor, growth factor, nerve growth factor and T-cell receptor-mediated signaling, implying a role of NR4A1 in cell proliferation (Bras et al., 2000). In addition, nerve growth factor IB and nuclear receptor subfamily 4 response elements, suggesting that NR4A1 functions in growth and cell cycle control (Pei et al., 2006). A dominant negative mutation in the transactivation domain of NR4A1 reduces cultured mouse embryonic cell growth in a tumor necrosis factor-dependent manner (Suzuki et al., 2003). Silencing of NR4A1 by siRNA treatment causes a dramatic reduction in growth/survival of HeLa, DLD1, HCT116, PC3, U87, and AsPC1 cell lines (Ke et al., 2004). Thus, NR4A1 appear to be involved in cell growth and survival, but the detailed mechanisms are still largely unknown.

Contradictory to its apparent role in cell survival, NR4A1 also activates several genes involved in cell apoptosis as well as translocating directly into mitochondria to enhance the apoptotic signal (Li et al., 2000; Lin et al., 2004; Zhang et al., 1999). For example, NR4A1 induces apoptosis in cultured prostate cancer cells through activation of the transcription factor E2F1 (Mu and Chang, 2003; Wilson et al., 2003). NR4A1 also mediates apoptosis through translocation from the nucleus into mitochondria where it interacted with the apoptosis regulating protein Bcl-2 to release cytochrome c (Lin et al., 2004; Suzuki et al., 2003). Another apoptosis regulating protein, BAX, is thought to recruit NR4A1 into the mitochondria to mediate apoptosis (Wilson et al., 2003). NR4A1 further induces apoptosis by reacting with self-recognizing major histocompatibility complex molecules in T cell (Zhang et al., 1999). NR4A1 acts as an inflammatory factor in T-cell, and T-cell receptor-mediated apoptosis can be prevented by inhibiting NR4A1 function (Liu et al., 1994; Woronicz et al., 1994). Thus, it appears that NR4A1 plays different and opposing roles in cell survival and apoptosis depending on the cell status and molecular environment (Mohan et al., 2012).

Neuronal regulation
GFP-tagged NR4A1 is associated with dopamine receptor D1 positive neurons in brain tissue of transgenic mice (Davis and Puhl, 2011). NR4A1 activity closely correlates with dopamine neurotransmission in the central nervous system of mice (Gilbert et al., 2006). Furthermore, NR4A1 induces immediate early genes within central nervous system cells and basal ganglia of adult mice (Heiman et al., 2008; Lobo et al., 2006). NR4A1 deficient mice exhibit dysfunctional locomotor behavior due to alteration of dopamine neuron activity (Gilbert et al., 2006). Although NR4A1 is clearly involved in dopamine neuron activity, the specific mechanisms of this involvement remain unknown (Perlmann and Wallen-Mackenzie, 2004).

Muscle homeostasis and metabolism
In skeletal muscle, NR4A1 expression is enhanced by activation of the beta-adrenergic signaling pathway during muscle hypertrophy and endurance exercise (Mahoney et al., 2005; Maxwell et al., 2005; Pearen et al., 2006). Knockdown of NR4A1 by siRNA treatment causes repression of several genes associated with lipid, carbohydrate and glucose metabolism including the genes for AMP-activated protein kinase subunit gamma 3, fatty acid translocase and glucose transporter 4 (Maxwell et al., 2005; Chao et al., 2007). Interestingly, NR4A1 appears to influence energy balance and thermogenesis control through uncoupling of mitochondrial respiration (Kanzleiter et al., 2005). These findings suggest that NR4A1 is involved in energy metabolism and muscle energetics and function.


NR4A1 is an evolutionarily conserved gene and shows similar genomic synteny across species. The NR4A family includes three proteins (NR4A1, NR4A2 and NR4A3) with highly conserved protein sequences (NCBI).



No single site, nonsense or frameshift mutations in NR4A1 have been associated with cancer and/or disease in humans, but disruption of NR4A1 in mice by insertion of the neomycin resistance gene in exon 2 leads to development of acute myeloid leukemia (Mullican et al., 2007).

Implicated in

Entity name
Cancer and clinical translation
It is well known that tumor growth depends on new blood vessel formation to facilitate nutrient delivery (Liu et al., 2003; Mohan et al., 2012). NR4A1 expression is enhanced by vascular endothelial growth factor (Arkenbout et al., 2003; Liu et al., 2003). VEGF also stimulates CREB-dependent NR4A1 expression which in turn enhances angiogenesis through its transcription factor activity (Zeng et al., 2006; Zhao et al., 2011b). In addition, NR4A1 is activated by overexpression of hypoxia-inducible factor-1 alpha and thereby promotes overproduction of the hormone precursor proopiomelanocortin in VHL-mutated renal cell carcinoma (Choi et al., 2004).
Although the studies cited above indicate that NR4A1 contributes to carcinogenesis, many others report the opposite effect of NR4A1 on tumor growth (Mohan et al., 2012). NR4A1 expression is modified to inhibit tumor formation in many tumor types, including colon, breast, bladder, liver, thyroid, lung, prostate, and renal cell carcinoma (Choi et al., 2004; Mohan et al., 2012; Mu and Chang, 2003). As noted earlier, NR4A1 promotes apoptosis in a human prostate cancer cell line through stimulation of E2F1 expression (Mu and Chang, 2003). Early induction of NR4A1 in a human breast cancer cell line causes A23187-induced cell death via the CREB signaling pathway (Ohkubo et al., 2000). Recruitment of NR4A1 to the mitochondria and the subsequent release of cytochrome c have been associated with the Bcl-2 apoptotic pathway in several different cancer cell types (Lin et al., 2004; Wilson et al., 2003). NR4A1 enhances p53 transactivation of ionizing radiation-induced apoptosis in hepatoma cells, indicating that it may be a potential target for cancer radiotherapy (Zhao et al., 2011a). Loss of NR4A1 correlates with malignancy in follicular thyroid carcinomas presumably due to the reduction in apoptosis that allows cell growth (Camacho et al., 2009). Retinoic acid receptors (RARs) are often lost during carcinogenesis. NR4A1 was found to form apoptosis-inducing heterodimers with RARs in cultured lung cancer cells (Wu et al., 1997). Up-regulation of NR4A1 and the resulting increase in apoptosis of human hepatocellular carcinoma cells is also RARβ dependent (Yang et al., 2011).
NR4A1 has begun to be incorporated into new cancer therapeutic strategies. These therapies rely on apoptosis induced by NR4A1 mitochondrial localization (Lin et al., 2004; Mohan et al., 2012). For example, glioblastoma multiforme is inhibited by local interstitial delivery of z-butylidenephthalide, which enhances NR4A1 expression and translocation into mitochondria (Harn et al., 2011; Lin et al., 2008). N-butylidenephthalide derivative also inhibit cell growth in hepatocellular carcinoma, oral squamous cell carcinoma and balloon injured rat carotid artery by inducing apoptosis (Chen et al., 2008; Liu et al., 2011; Liu et al., 2012). Moreover, 1,1-Bis(3-indolyl)-1-(p-substituted phenyl)methanes induce apoptosis through NR4A1 activation in cultured pancreatic carcinoma cells (Chintharlapalli et al., 2005).


Pubmed IDLast YearTitleAuthors
128428392003TR3 orphan receptor is expressed in vascular endothelial cells and mediates cell cycle arrest.Arkenbout EK et al
151934512004Structure and function of the glucocorticoid receptor ligand binding domain.Bledsoe RK et al
107452712000Ceramide-induced cell death is independent of the Fas/Fas ligand pathway and is prevented by Nur77 overexpression in A20 B cells.Brás A et al
187277082009Down-regulation of NR4A1 in follicular thyroid carcinomas is restored following lithium treatment.Camacho CP et al
175509772007Nur77 coordinately regulates expression of genes linked to glucose metabolism in skeletal muscle.Chao LC et al
185776872008The induction of orphan nuclear receptor Nur77 expression by n-butylenephthalide as pharmaceuticals on hepatocellular carcinoma cell therapy.Chen YL et al
158719452005Activation of Nur77 by selected 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes induces apoptosis through nuclear pathways.Chintharlapalli S et al
147296052004Nur77 activated by hypoxia-inducible factor-1alpha overproduces proopiomelanocortin in von Hippel-Lindau-mutated renal cell carcinoma.Choi JW et al
81646921994Endocrine and neurogenic regulation of the orphan nuclear receptors Nur77 and Nurr-1 in the adrenal glands.Davis IJ et al
213050522011Nr4a1-eGFP is a marker of striosome-matrix architecture, development and activity in the extended striatum.Davis MI et al
168935302006Nur77 gene knockout alters dopamine neuron biochemical activity and dopamine turnover.Gilbert F et al
215658412011Local interstitial delivery of z-butylidenephthalide by polymer wafers against malignant human gliomas.Harn HJ et al
190132812008A translational profiling approach for the molecular characterization of CNS cell types.Heiman M et al
204387162010Regulation of Nur77 protein turnover through acetylation and deacetylation induced by p300 and HDAC1.Kang SA et al
162198682005Evidence for Nr4a1 as a cold-induced effector of brown fat thermogenesis.Kanzleiter T et al
155486862004Nuclear hormone receptor NR4A2 is involved in cell transformation and apoptosis.Ke N et al
111798902001Zinc finger proteins: new insights into structural and functional diversity.Laity JH et al
212047312011Targeting NR4A1 (TR3) in cancer cells and tumors.Lee SO et al
109479772000Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3.Li H et al
164935832006NR4A1, 2, 3--an orphan nuclear hormone receptor family involved in cell apoptosis and carcinogenesis.Li QX et al
149802202004Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3.Lin B et al
184197612008Orphan nuclear receptor, Nurr-77 was a possible target gene of butylidenephthalide chemotherapy on glioblastoma multiform brain tumor.Lin PC et al
145257952003Vascular endothelial growth factor-regulated gene expression in endothelial cells: KDR-mediated induction of Egr3 and the related nuclear receptors Nur77, Nurr1, and Nor1.Liu D et al
208092062012Expression of Nur77 induced by an n-butylidenephthalide derivative promotes apoptosis and inhibits cell growth in oral squamous cell carcinoma.Liu PY et al
213657112011Inhibitory effect of n-butylidenephthalide on neointimal hyperplasia in balloon injured rat carotid artery.Liu WS et al
81214941994Apoptotic signals delivered through the T-cell receptor of a T-cell hybrid require the immediate-early gene nur77.Liu ZG et al
164910812006FACS-array profiling of striatal projection neuron subtypes in juvenile and adult mouse brains.Lobo MK et al
159855252005Analysis of global mRNA expression in human skeletal muscle during recovery from endurance exercise.Mahoney DJ et al
156401432005Nur77 regulates lipolysis in skeletal muscle cells. Evidence for cross-talk between the beta-adrenergic and an orphan nuclear hormone receptor pathway.Maxwell MA et al
214289632011Inflammation: a role for NR4A orphan nuclear receptors?McMorrow JP et al
152423412004Gene repression by nuclear hormone receptors.Moehren U et al
225663772012Molecular pathways: the role of NR4A orphan nuclear receptors in cancer.Mohan HM et al
129471202003TR3 orphan nuclear receptor mediates apoptosis through up-regulating E2F1 in human prostate cancer LNCaP cells.Mu X et al
175158972007Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia.Mullican SE et al
108547082000Early induction of the orphan nuclear receptor NOR-1 during cell death of the human breast cancer cell line MCF-7.Ohkubo T et al
169019672006The orphan nuclear receptor, NOR-1, is a target of beta-adrenergic signaling in skeletal muscle.Pearen MA et al
163392772006Regulation of macrophage inflammatory gene expression by the orphan nuclear receptor Nur77.Pei L et al
112743862001Akt phosphorylates and regulates the orphan nuclear receptor Nur77.Pekarsky Y et al
153408332004Nurr1, an orphan nuclear receptor with essential functions in developing dopamine cells.Perlmann T et al
150753902004A gene atlas of the mouse and human protein-encoding transcriptomes.Su AI et al
128151082003Nur77 as a survival factor in tumor necrosis factor signaling.Suzuki S et al
145003742003TR3/Nur77 in colon cancer cell apoptosis.Wilson AJ et al
81214931994Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas.Woronicz JD et al
91307111997Modulation of retinoic acid sensitivity in lung cancer cells through dynamic balance of orphan receptors nur77 and COUP-TF and their heterodimerization.Wu Q et al
120328312002Promyelocytic leukemia protein PML inhibits Nur77-mediated transcription through specific functional interactions.Wu WS et al
213191872011Enrichment of Nur77 mediated by retinoic acid receptor β leads to apoptosis of human hepatocellular carcinoma cells induced by fenretinide and histone deacetylase inhibitors.Yang H et al
165203882006Orphan nuclear receptor TR3/Nur77 regulates VEGF-A-induced angiogenesis through its transcriptional activity.Zeng H et al
112323091999Receptor-mediated apoptosis in T lymphocytes.Zhang J et al
216594762011Orphan receptor TR3 enhances p53 transactivation and represses DNA double-strand break repair in hepatoma cells under ionizing radiation.Zhao BX et al
207151162011VEGF stimulates PKD-mediated CREB-dependent orphan nuclear receptor Nurr1 expression: role in VEGF-induced angiogenesis.Zhao D et al
212779782012NR4All in the vessel wall.van Tiel CM et al

Other Information

Locus ID:

NCBI: 3164
MIM: 139139
HGNC: 7980
Ensembl: ENSG00000123358


dbSNP: 3164
ClinVar: 3164
TCGA: ENSG00000123358


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
MAPK signaling pathwayKEGGhsa04010
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Diseases of signal transductionREACTOMER-HSA-5663202
PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
Constitutive Signaling by AKT1 E17K in CancerREACTOMER-HSA-5674400
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
AKT phosphorylates targets in the nucleusREACTOMER-HSA-198693
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GAB1 signalosomeREACTOMER-HSA-180292
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by SCF-KITREACTOMER-HSA-1433557
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Nuclear Receptor transcription pathwayREACTOMER-HSA-383280
Aldosterone synthesis and secretionKEGGhsa04925
Aldosterone synthesis and secretionKEGGko04925

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
149802202004Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3.210
175158972007Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia.116
159648442005Induction of NR4A orphan nuclear receptor expression in macrophages in response to inflammatory stimuli.87
168737292006Nuclear receptors Nur77, Nurr1, and NOR-1 expressed in atherosclerotic lesion macrophages reduce lipid loading and inflammatory responses.81
119831532002Nuclear hormone receptors in T lymphocytes.78
146124082003Mitogenic effect of orphan receptor TR3 and its regulation by MEKK1 in lung cancer cells.73
155097762004Retinoid X receptor regulates Nur77/TR3-dependent apoptosis [corrected] by modulating its nuclear export and mitochondrial targeting.61
158719452005Activation of Nur77 by selected 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes induces apoptosis through nuclear pathways.55
145257952003Vascular endothelial growth factor-regulated gene expression in endothelial cells: KDR-mediated induction of Egr3 and the related nuclear receptors Nur77, Nurr1, and Nor1.48
229831572012The orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPK.47


Tzu-Min Chan ; Shinn-Zong Lin ; Tzyy-Wen Chiou ; Horng-Jyh Harn

NR4A1 (nuclear receptor subfamily 4, group A, member 1)

Atlas Genet Cytogenet Oncol Haematol. 2013-01-01

Online version: