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

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Review
NR4A1 (nuclear receptor subfamily 4, group A,
member 1)
Tzu-Min Chan, Shinn-Zong Lin, Tzyy-Wen Chiou, Horng-Jyh Harn
Center for Neuropsychiatry, China Medical University and Hospital, Taichung, 40447, Taiwan, ROC and
Everfront Biotech Inc., F11, No 31, Ln169, Kangning St., Xizhi Dist., New Taipei City 221, Taiwan, ROC
(TMC), Center for Neuropsychiatry, China Medical University and Hospital, Taichung, 40447, Taiwan,
ROC (SZL), Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa
University, Hualien, Taiwan, ROC (TWC), Department of Pathology, China Medical University Hospital,
and Department of Medicine, China Medical University, Taichung, Taiwan, ROC (HJH)
Published in Atlas Database: January 2013
Online updated version : http://AtlasGeneticsOncology.org/Genes/NR4A1ID41573ch12q13.html
DOI: 10.4267/2042/51041
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Variant 3 mRNA
NM_001202233.
Identity
Other names: GFRP1, HMR, N10, NAK-1, NGFIB,
NP10, NUR77, TR3
HGNC (Hugo): NR4A1
Location: 12q13.13
Note
This article is an update of: NR4A1, 2, 3--an orphan
nuclear hormone receptor family involved in cell
apoptosis and carcinogenesis (Li et al., 2006).
Reference
number:
Protein
Description
NR4A1 is a steroid/thyroid hormone-responsive orphan
nuclear receptor that contains three key functional
domains: a steroid hormone receptor ligandindependent 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).
DNA/RNA
Description
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).
Transcription
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.
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(7)
NCBI
457
NR4A1 (nuclear receptor subfamily 4, group A, member 1)
Chan TM, et al.
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.
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.
Apoptosis
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.,
Expression
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).
Localisation
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).
Function
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.,
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(7)
458
NR4A1 (nuclear receptor subfamily 4, group A, member 1)
Chan TM, et al.
NR4A3) with highly conserved protein sequences
(NCBI).
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.
Mutations
Note
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
Cancer and clinical translation
Note
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
Homology
NR4A1 is an evolutionarily conserved gene and shows
similar genomic synteny across species. The NR4A
family includes three proteins (NR4A1, NR4A2 and
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(7)
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NR4A1 (nuclear receptor subfamily 4, group A, member 1)
Chan TM, et al.
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). Nbutylidenephthalide 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-(psubstituted phenyl)methanes induce apoptosis through
NR4A1 activation in cultured pancreatic carcinoma
cells (Chintharlapalli et al., 2005).
Laity JH, Lee BM, Wright PE. Zinc finger proteins: new insights
into structural and functional diversity. Curr Opin Struct Biol.
2001 Feb;11(1):39-46
To be noted
Mu X, Chang C. TR3 orphan nuclear receptor mediates
apoptosis through up-regulating E2F1 in human prostate
cancer LNCaP cells. J Biol Chem. 2003 Oct 31;278(44):428405
Pekarsky Y, Hallas C, Palamarchuk A, Koval A, Bullrich F,
Hirata Y, Bichi R, Letofsky J, Croce CM. Akt phosphorylates
and regulates the orphan nuclear receptor Nur77. Proc Natl
Acad Sci U S A. 2001 Mar 27;98(7):3690-4
Wu WS, Xu ZX, Ran R, Meng F, Chang KS. Promyelocytic
leukemia protein PML inhibits Nur77-mediated transcription
through specific functional interactions. Oncogene. 2002 May
30;21(24):3925-33
Arkenbout EK, van Bragt M, Eldering E, van Bree C,
Grimbergen JM, Quax PH, Pannekoek H, de Vries CJ. TR3
orphan receptor is expressed in vascular endothelial cells and
mediates cell cycle arrest. Arterioscler Thromb Vasc Biol. 2003
Sep 1;23(9):1535-40
Liu D, Jia H, Holmes DI, Stannard A, Zachary I. Vascular
endothelial growth factor-regulated gene expression in
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related nuclear receptors Nur77, Nurr1, and Nor1. Arterioscler
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Note
Acknowledgements, Taiwan Department of Health
Clinical Trial and Research Center of Excellence
(DOH101-TD-B-111-004).
Suzuki S, Suzuki N, Mirtsos C, Horacek T, Lye E, Noh SK, Ho
A, Bouchard D, Mak TW, Yeh WC. Nur77 as a survival factor
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Chan TM, Lin SZ, Chiou TW, Harn HJ. NR4A1 (nuclear
receptor subfamily 4, group A, member 1). Atlas Genet
Cytogenet Oncol Haematol. 2013; 17(7):457-461.
Lin PC, Chen YL, Chiu SC, Yu YL, Chen SP, Chien MH, Chen
KY, Chang WL, Lin SZ, Chiou TW, Harn HJ. Orphan nuclear
receptor, Nurr-77 was a possible target gene of
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