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

Written2013-01Tzu-Min Chan, Shinn-Zong Lin, Tzyy-Wen Chiou, Horng-Jyh Harn
Center for Neuropsychiatry, China Medical University, Hospital, Taichung, 40447, Taiwan, ROC (TMC, SZL); Everfront Biotech Inc., F11, No 31, Ln169, Kangning St., Xizhi Dist., New Taipei City 221, Taiwan, ROC (TMC); Department of Life Science, Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, ROC (TWC); Department of Pathology, China Medical University Hospital,, Department of Medicine, China Medical University, Taichung, Taiwan, ROC (HJH)

(Note : for Links provided by Atlas : click)

Identity

Alias_namesHMR
GFRP1
nuclear receptor subfamily 4
Alias_symbol (synonym)TR3
N10
NAK-1
NGFIB
NUR77
HGNC (Hugo) NR4A1
LocusID (NCBI) 3164
Atlas_Id 41573
Location 12q13.13  [Link to chromosome band 12q13]
Location_base_pair Starts at 52416616 and ends at 52453291 bp from pter ( according to hg19-Feb_2009)  [Mapping NR4A1.png]
Fusion genes
(updated 2016)
AKAP2 (9q31.3) / NR4A1 (12q13.13)ANAPC16 (10q22.1) / NR4A1 (12q13.13)CLASP1 (2q14.2) / NR4A1 (12q13.13)
HNRNPUL2 (11q12.3) / NR4A1 (12q13.13)IL20RB (3q22.3) / NR4A1 (12q13.13)METRN (16p13.3) / NR4A1 (12q13.13)
NR4A1 (12q13.13) / IFRD2 (3p21.31)NR4A1 (12q13.13) / IL20RB (3q22.3)NR4A1 (12q13.13) / NR4A1 (12q13.13)
NR4A1 (12q13.13) / TMPRSS2 (21q22.3)PABPC1 (8q22.3) / NR4A1 (12q13.13)PDE9A (21q22.3) / NR4A1 (12q13.13)
SFPQ (16q24.1) / NR4A1 (12q13.13)TXNL4B (16q22.2) / NR4A1 (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).

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.
Variant 3 mRNA NCBI Reference number: NM_001202233.

Protein

 
  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.
Description 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).
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., 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., 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.

Homology 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).

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

Note
Entity 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 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).
  

To be noted

Acknowledgements, Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH101-TD-B-111-004).

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Citation

This paper should be referenced as such :
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.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/NR4A1ID41573ch12q13.html


External links

Nomenclature
HGNC (Hugo)NR4A1   7980
Cards
AtlasNR4A1ID41573ch12q13
Entrez_Gene (NCBI)NR4A1  3164  nuclear receptor subfamily 4 group A member 1
AliasesGFRP1; HMR; N10; NAK-1; 
NGFIB; NP10; NUR77; TR3
GeneCards (Weizmann)NR4A1
Ensembl hg19 (Hinxton)ENSG00000123358 [Gene_View]  chr12:52416616-52453291 [Contig_View]  NR4A1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000123358 [Gene_View]  chr12:52416616-52453291 [Contig_View]  NR4A1 [Vega]
ICGC DataPortalENSG00000123358
TCGA cBioPortalNR4A1
AceView (NCBI)NR4A1
Genatlas (Paris)NR4A1
WikiGenes3164
SOURCE (Princeton)NR4A1
Genetics Home Reference (NIH)NR4A1
Genomic and cartography
GoldenPath hg19 (UCSC)NR4A1  -     chr12:52416616-52453291 +  12q13.13   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)NR4A1  -     12q13.13   [Description]    (hg38-Dec_2013)
EnsemblNR4A1 - 12q13.13 [CytoView hg19]  NR4A1 - 12q13.13 [CytoView hg38]
Mapping of homologs : NCBINR4A1 [Mapview hg19]  NR4A1 [Mapview hg38]
OMIM139139   
Gene and transcription
Genbank (Entrez)AB307717 AK075054 AK075491 AK096816 AK131566
RefSeq transcript (Entrez)NM_001202233 NM_001202234 NM_002135 NM_173157 NM_173158
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)NR4A1
Cluster EST : UnigeneHs.670088 [ NCBI ]
CGAP (NCI)Hs.670088
Alternative Splicing GalleryENSG00000123358
Gene ExpressionNR4A1 [ NCBI-GEO ]   NR4A1 [ EBI - ARRAY_EXPRESS ]   NR4A1 [ SEEK ]   NR4A1 [ MEM ]
Gene Expression Viewer (FireBrowse)NR4A1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)3164
GTEX Portal (Tissue expression)NR4A1
Protein : pattern, domain, 3D structure
UniProt/SwissProtP22736   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP22736  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP22736
Splice isoforms : SwissVarP22736
PhosPhoSitePlusP22736
Domaine pattern : Prosite (Expaxy)NUCLEAR_REC_DBD_1 (PS00031)    NUCLEAR_REC_DBD_2 (PS51030)   
Domains : Interpro (EBI)Nuc_orp_HMR_rcpt    Nuc_orph_rcpt    Nucl_hrmn_rcpt_lig-bd    Nuclear_hrmn_rcpt    Znf_hrmn_rcpt    Znf_NHR/GATA   
Domain families : Pfam (Sanger)Hormone_recep (PF00104)    zf-C4 (PF00105)   
Domain families : Pfam (NCBI)pfam00104    pfam00105   
Domain families : Smart (EMBL)HOLI (SM00430)  ZnF_C4 (SM00399)  
Conserved Domain (NCBI)NR4A1
DMDM Disease mutations3164
Blocks (Seattle)NR4A1
PDB (SRS)2QW4    3V3E    3V3Q    4JGV    4KZI    4KZJ    4KZM    4RE8    4REE    4REF    4RZE    4RZF    4RZG    4WHF    4WHG   
PDB (PDBSum)2QW4    3V3E    3V3Q    4JGV    4KZI    4KZJ    4KZM    4RE8    4REE    4REF    4RZE    4RZF    4RZG    4WHF    4WHG   
PDB (IMB)2QW4    3V3E    3V3Q    4JGV    4KZI    4KZJ    4KZM    4RE8    4REE    4REF    4RZE    4RZF    4RZG    4WHF    4WHG   
PDB (RSDB)2QW4    3V3E    3V3Q    4JGV    4KZI    4KZJ    4KZM    4RE8    4REE    4REF    4RZE    4RZF    4RZG    4WHF    4WHG   
Structural Biology KnowledgeBase2QW4    3V3E    3V3Q    4JGV    4KZI    4KZJ    4KZM    4RE8    4REE    4REF    4RZE    4RZF    4RZG    4WHF    4WHG   
SCOP (Structural Classification of Proteins)2QW4    3V3E    3V3Q    4JGV    4KZI    4KZJ    4KZM    4RE8    4REE    4REF    4RZE    4RZF    4RZG    4WHF    4WHG   
CATH (Classification of proteins structures)2QW4    3V3E    3V3Q    4JGV    4KZI    4KZJ    4KZM    4RE8    4REE    4REF    4RZE    4RZF    4RZG    4WHF    4WHG   
SuperfamilyP22736
Human Protein AtlasENSG00000123358
Peptide AtlasP22736
HPRD00744
IPIIPI00743108   IPI00027454   IPI01011914   IPI00027914   IPI01021025   IPI00978792   
Protein Interaction databases
DIP (DOE-UCLA)P22736
IntAct (EBI)P22736
FunCoupENSG00000123358
BioGRIDNR4A1
STRING (EMBL)NR4A1
ZODIACNR4A1
Ontologies - Pathways
QuickGOP22736
Ontology : AmiGOtranscriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  positive regulation of endothelial cell proliferation  cell migration involved in sprouting angiogenesis  DNA binding  steroid hormone receptor activity  RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding  protein binding  nucleus  nucleus  nucleoplasm  cytoplasm  transcription initiation from RNA polymerase II promoter  signal transduction  zinc ion binding  intracellular receptor signaling pathway  nuclear membrane  endothelial cell chemotaxis  cellular response to vascular endothelial growth factor stimulus  steroid hormone mediated signaling pathway  sequence-specific DNA binding  cellular response to fibroblast growth factor stimulus  fat cell differentiation  negative regulation of cell cycle  positive regulation of transcription from RNA polymerase II promoter  protein heterodimerization activity  regulation of type B pancreatic cell proliferation  cellular response to corticotropin-releasing hormone stimulus  
Ontology : EGO-EBItranscriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  positive regulation of endothelial cell proliferation  cell migration involved in sprouting angiogenesis  DNA binding  steroid hormone receptor activity  RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding  protein binding  nucleus  nucleus  nucleoplasm  cytoplasm  transcription initiation from RNA polymerase II promoter  signal transduction  zinc ion binding  intracellular receptor signaling pathway  nuclear membrane  endothelial cell chemotaxis  cellular response to vascular endothelial growth factor stimulus  steroid hormone mediated signaling pathway  sequence-specific DNA binding  cellular response to fibroblast growth factor stimulus  fat cell differentiation  negative regulation of cell cycle  positive regulation of transcription from RNA polymerase II promoter  protein heterodimerization activity  regulation of type B pancreatic cell proliferation  cellular response to corticotropin-releasing hormone stimulus  
Pathways : KEGGMAPK signaling pathway    PI3K-Akt signaling pathway   
REACTOMEP22736 [protein]
REACTOME PathwaysR-HSA-5674400 [pathway]
NDEx NetworkNR4A1
Atlas of Cancer Signalling NetworkNR4A1
Wikipedia pathwaysNR4A1
Orthology - Evolution
OrthoDB3164
GeneTree (enSembl)ENSG00000123358
Phylogenetic Trees/Animal Genes : TreeFamNR4A1
HOVERGENP22736
HOGENOMP22736
Homologs : HomoloGeneNR4A1
Homology/Alignments : Family Browser (UCSC)NR4A1
Gene fusions - Rearrangements
Fusion : MitelmanIL20RB/NR4A1 [3q22.3/12q13.13]  [t(3;12)(q22;q13)]  
Fusion : MitelmanNR4A1/IL20RB [12q13.13/3q22.3]  [t(3;12)(q22;q13)]  
Fusion: TCGAIL20RB 3q22.3 NR4A1 12q13.13 HNSC
Fusion: TCGANR4A1 12q13.13 IL20RB 3q22.3 HNSC
Fusion Cancer (Beijing)NR4A1 [12q13.13]  -  TMPRSS2 [21q22.3]  [FUSC004214]
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerNR4A1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)NR4A1
dbVarNR4A1
ClinVarNR4A1
1000_GenomesNR4A1 
Exome Variant ServerNR4A1
ExAC (Exome Aggregation Consortium)NR4A1 (select the gene name)
Genetic variants : HAPMAP3164
Genomic Variants (DGV)NR4A1 [DGVbeta]
DECIPHER (Syndromes)12:52416616-52453291  ENSG00000123358
CONAN: Copy Number AnalysisNR4A1 
Mutations
ICGC Data PortalNR4A1 
TCGA Data PortalNR4A1 
Broad Tumor PortalNR4A1
OASIS PortalNR4A1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICNR4A1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDNR4A1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch NR4A1
DgiDB (Drug Gene Interaction Database)NR4A1
DoCM (Curated mutations)NR4A1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)NR4A1 (select a term)
intoGenNR4A1
NCG5 (London)NR4A1
Cancer3DNR4A1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM139139   
Orphanet
MedgenNR4A1
Genetic Testing Registry NR4A1
NextProtP22736 [Medical]
TSGene3164
GENETestsNR4A1
Huge Navigator NR4A1 [HugePedia]
snp3D : Map Gene to Disease3164
BioCentury BCIQNR4A1
ClinGenNR4A1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD3164
Chemical/Pharm GKB GenePA31761
Clinical trialNR4A1
Miscellaneous
canSAR (ICR)NR4A1 (select the gene name)
Probes
Litterature
PubMed187 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineNR4A1
EVEXNR4A1
GoPubMedNR4A1
iHOPNR4A1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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