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IER3 (immediate early response 3)

Written2009-12Heiner Schäfer, Alexander Arlt
1st Department of Medicine, UKSH Campus Kiel, Schittenhelmstr. 12, 24105 Kiel, Germany

(Note : for Links provided by Atlas : click)


Alias (NCBI)DIF-2
HGNC (Hugo) IER3
HGNC Alias symbIEX-1
LocusID (NCBI) 8870
Atlas_Id 40919
Location 6p21.33  [Link to chromosome band 6p21]
Location_base_pair Starts at 30743199 and ends at 30744547 bp from pter ( according to hg19-Feb_2009)  [Mapping IER3.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
AMPD3 (11p15.4) / IER3 (6p21.33)ATP6V0A1 (17q21.2) / IER3 (6p21.33)SLC39A7 (6p21.32) / IER3 (6p21.33)


  The IER3 pre-mRNA contains two exons and one intron (112 bp). cds: coding strand; 5'UTR: 5'untranslated region; 3'UTR: 3'untranslated region, ARE: A-rich element.
Description The IER3 gene spans 1351 bp genomic DNA and consists of 2 coding exons. The coding sequence of IER3 is 498 nucleotides long.


  The IER3 protein contains several potential ERK phosphorylation sites - one functionally verified on Thr18 (P) (Garcia et al., 2002), a PEST like sequence a functional nuclear localization sequence (NLS) (Kruse et al., 2005), a potential transmembrane domain (TM) and a N-linked glycosylation site (NLG).
Description IER3 as well as its rodent homologues PRG1 and gly96 consists of 156, 160 and 153 amino acids, respectively, and, to current knowledge, share no significant sequence similarities with any other known protein. IER3 shuttles between the cytoplasm and the nucleus (Kruse et al., 2005) where it accumulates in promyelocytic nuclear dots, unique structures that are involved in stress response. IER3 is also localized in the mitochondrial membrane where it interferes with the ATP producing system (Shen et al., 2009).
Expression Epithelial cells, keratinocytes, hepatocytes, monocytes, lymphocytes.
Localisation Nucleus, mitochondrial membrane, cytoplasm.
Function Immediate early gene X-1 (IEX-1), also known as IER3/DIF2, is a growth and stress associated early response gene (Kondratyev et al., 1996; Schäfer et al., 1996) involved in a great variety of cellular functions (Wu, 2003). The expression of IER3 is under control of many stimuli and cellular conditions including growth factors, cytokines, viral infection, UV- and gamma-irradiation or biomechanical strain. Recent data demonstrated that IER3 modulates cell cycle progression and proliferation, as well as programmed cell death in a cell type- and stimulus-dependent fashion (Wu, 2003).
A line of functional studies revealed that IER3 exerts a dual role in cellular growth control and apoptosis. For example, in epithelial cells, hepatocytes and keratinocytes IER3 enhances apoptosis (Schilling et al., 2001; Arlt et al., 2007; Arlt et al., 2008; Sebens Muerkoster et al., 2008) whereas in hematological precursor cells and in immune cells IER3 rather favours cellular survival and differentiation (Wu, 2003; Mittal et al., 2006; Rocher et al., 2007; Rocher et al., 2007).
Recent studies revealed that IER3 expression is inversely related to the formation of malignant tumors such as colon cancer (Nambiar et al., 2004; Sebens Muerkoster et al., 2008), pancreatic cancer (Sasada et al., 2008) and endocrine tumors (Dilley et al., 2005), thus pointing to a tumor suppressive potential of IER3. Obviously, the cellular actions of IER3 are complex depending on cell type and context related conditions but one mechanism by which IER3 could affect cellular viability is the negative interference with NF-kappaB activation. To some extent this action of IER3 relies on the dampening of IkappaB degradation thereby leading to a reduced nuclear localization of NF-kappaB (Arlt et al., 2001; Arlt et al., 2003; Arlt et al., 2007).
Moreover, a recent study demonstrated that IER3 is also capable to directly bind to p65/RelA leading to the inhibition of p65-dependent gene transcription (Arlt et al., 2008). Thus, IER3 is supposed to be part of a NF-kappaB dependent counterregulatory mechanism that might be particularly relevant in the control of immune responses.
Consequently, an impaired NF-kappaB control may promote severe inflammatory processes and carcinogenesis.
Homology None.


Note IEX-1L : Non spliced variant encoding the apoptosis inhibitor IEX-1L (Wu et al., 1998). This gene product does not derive from regular pre-mRNA splicing nor from a second gene but represents a triple mutated form of IEX-1/IER3 (Schäfer et al., 1999). This mutant variant has been artificially produced and acts as a dominant negative suppressor of wild type IEX-1/IER3 (Schäfer et al., 1999).
  Due to triple point-mutations a variant of IER3 has lost a splicing site and encodes for a protein of 183 amino acids containing an in-frame 37 amino acids insertion (IEX-1L).

Implicated in

Entity Colon cancer
Disease IER3 expression is inversely related to the formation of colon cancer (Nambiar et al., 2004; Sebens Muerkoster et al., 2008) and IER3 expression is lost during aberrant crypt formation in the murine colon (Nambiar et al., 2004)
Entity Pancreatic cancer
Disease IER3 expression is inversely related to the formation of pancreatic cancer (Sasada et al., 2008). In pancreatic cancer, IER3 expression associates with poor prognosis (Sasada et al., 2008).
Entity Multiple Endocrine Neoplasia type 1 (MEN1) tumors
Disease IER3 expression is inversely related to the formation of endocrine tumors (Dilley et al., 2005).


Expression of the NF-kappa B target gene IEX-1 (p22/PRG1) does not prevent cell death but instead triggers apoptosis in Hela cells.
Arlt A, Grobe O, Sieke A, Kruse ML, Folsch UR, Schmidt WE, Schafer H.
Oncogene. 2001 Jan 4;20(1):69-76.
PMID 11244505
The early response gene IEX-1 attenuates NF-kappaB activation in 293 cells, a possible counter-regulatory process leading to enhanced cell death.
Arlt A, Kruse ML, Breitenbroich M, Gehrz A, Koc B, Minkenberg J, Folsch UR, Schafer H.
Oncogene. 2003 May 22;22(21):3343-51.
PMID 12761504
Immediate early gene-X1 interferes with 26 S proteasome activity by attenuating expression of the 19 S proteasomal components S5a/Rpn10 and S1/Rpn2.
Arlt A, Minkenberg J, Kruse ML, Grohmann F, Folsch UR, Schafer H.
Biochem J. 2007 Mar 1;402(2):367-75.
PMID 17107344
IEX-1 directly interferes with RelA/p65 dependent transactivation and regulation of apoptosis.
Arlt A, Rosenstiel P, Kruse ML, Grohmann F, Minkenberg J, Perkins ND, Folsch UR, Schreiber S, Schafer H.
Biochim Biophys Acta. 2008 May;1783(5):941-52. Epub 2007 Dec 23.
PMID 18191642
Global gene expression in neuroendocrine tumors from patients with the MEN1 syndrome.
Dilley WG, Kalyanaraman S, Verma S, Cobb JP, Laramie JM, Lairmore TC.
Mol Cancer. 2005 Feb 3;4(1):9.
PMID 15691381
IEX-1: a new ERK substrate involved in both ERK survival activity and ERK activation.
Garcia J, Ye Y, Arranz V, Letourneux C, Pezeron G, Porteu F.
EMBO J. 2002 Oct 1;21(19):5151-63.
PMID 12356731
Identification and characterization of a radiation-inducible glycosylated human early-response gene.
Kondratyev AD, Chung KN, Jung MO.
Cancer Res. 1996 Apr 1;56(7):1498-502.
PMID 8603392
Immediate early gene X1 (IEX-1) is organized in subnuclear structures and partially co-localizes with promyelocytic leukemia protein in HeLa cells.
Kruse ML, Arlt A, Sieke A, Grohmann F, Grossmann M, Minkenberg J, Folsch UR, Schafer H.
J Biol Chem. 2005 Jul 1;280(26):24849-56. Epub 2005 Apr 26.
PMID 15855159
NF-kappaB-dependent regulation of the timing of activation-induced cell death of T lymphocytes.
Mittal A, Papa S, Franzoso G, Sen R.
J Immunol. 2006 Feb 15;176(4):2183-9.
PMID 16455974
Genetic signatures of high- and low-risk aberrant crypt foci in a mouse model of sporadic colon cancer.
Nambiar PR, Nakanishi M, Gupta R, Cheung E, Firouzi A, Ma XJ, Flynn C, Dong M, Guda K, Levine J, Raja R, Achenie L, Rosenberg DW.
Cancer Res. 2004 Sep 15;64(18):6394-401.
PMID 15374946
Inhibition of B56-containing protein phosphatase 2As by the early response gene IEX-1 leads to control of Akt activity.
Rocher G, Letourneux C, Lenormand P, Porteu F.
J Biol Chem. 2007 Feb 23;282(8):5468-77. Epub 2007 Jan 2.
PMID 17200115
Prognostic significance of the immediate early response gene X-1 (IEX-1) expression in pancreatic cancer.
Sasada T, Azuma K, Hirai T, Hashida H, Kanai M, Yanagawa T, Takabayashi A.
Ann Surg Oncol. 2008 Feb;15(2):609-17. Epub 2007 Nov 17.
PMID 18026799
The putative apoptosis inhibitor IEX-1L is a mutant nonspliced variant of p22(PRG1/IEX-1) and is not expressed in vivo.
Schafer H, Arlt A, Trauzold A, Hunermann-Jansen A, Schmidt WE.
Biochem Biophys Res Commun. 1999 Aug 19;262(1):139-45.
PMID 10448082
PRG1: a novel early-response gene transcriptionally induced by pituitary adenylate cyclase activating polypeptide in a pancreatic carcinoma cell line.
Schafer H, Trauzold A, Siegel EG, Folsch UR, Schmidt WE.
Cancer Res. 1996 Jun 1;56(11):2641-8.
PMID 8653710
IEX-1, an immediate early gene, increases the rate of apoptosis in keratinocytes.
Schilling D, Pittelkow MR, Kumar R.
Oncogene. 2001 Nov 29;20(55):7992-7.
PMID 11753682
The apoptosis-inducing effect of gastrin on colorectal cancer cells relates to an increased IEX-1 expression mediating NF-kappa B inhibition.
Sebens Muerkoster S, Rausch AV, Isberner A, Minkenberg J, Blaszczuk E, Witt M, Folsch UR, Schmitz F, Schafer H, Arlt A.
Oncogene. 2008 Feb 14;27(8):1122-34. Epub 2007 Aug 20.
PMID 17704804
IEX-1 targets mitochondrial F1Fo-ATPase inhibitor for degradation.
Shen L, Zhi L, Hu W, Wu MX.
Cell Death Differ. 2009 Apr;16(4):603-12. Epub 2008 Dec 19.
PMID 19096392
IEX-1L, an apoptosis inhibitor involved in NF-kappaB-mediated cell survival.
Wu MX, Ao Z, Prasad KV, Wu R, Schlossman SF.
Science. 1998 Aug 14;281(5379):998-1001.
PMID 9703517
Roles of the stress-induced gene IEX-1 in regulation of cell death and oncogenesis.
Wu MX.
Apoptosis. 2003 Jan;8(1):11-8.
PMID 12510147


This paper should be referenced as such :
Schè_fer, H ; Arlt, A
IER3 (immediate early response 3)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(9):885-888.
Free journal version : [ pdf ]   [ DOI ]

External links

HGNC (Hugo)IER3   5392
Entrez_Gene (NCBI)IER3  8870  immediate early response 3
AliasesDIF-2; DIF2; GLY96; IEX-1; 
GeneCards (Weizmann)IER3
Ensembl hg19 (Hinxton)ENSG00000137331 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000137331 [Gene_View]  ENSG00000137331 [Sequence]  chr6:30743199-30744547 [Contig_View]  IER3 [Vega]
ICGC DataPortalENSG00000137331
TCGA cBioPortalIER3
AceView (NCBI)IER3
Genatlas (Paris)IER3
SOURCE (Princeton)IER3
Genetics Home Reference (NIH)IER3
Genomic and cartography
GoldenPath hg38 (UCSC)IER3  -     chr6:30743199-30744547 -  6p21.33   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)IER3  -     6p21.33   [Description]    (hg19-Feb_2009)
GoldenPathIER3 - 6p21.33 [CytoView hg19]  IER3 - 6p21.33 [CytoView hg38]
genome Data Viewer NCBIIER3 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AF039067 AF083421 AJ227914 AK222588 AK314162
RefSeq transcript (Entrez)NM_003897 NM_052815
RefSeq genomic (Entrez)NC_000006 NT_113891 NT_167245 NT_167246 NT_167248 NT_167249
Consensus coding sequences : CCDS (NCBI)IER3
Alternative Splicing GalleryENSG00000137331
Gene ExpressionIER3 [ NCBI-GEO ]   IER3 [ EBI - ARRAY_EXPRESS ]   IER3 [ SEEK ]   IER3 [ MEM ]
Gene Expression Viewer (FireBrowse)IER3 [ Firebrowse - Broad ]
GenevisibleExpression of IER3 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)8870
GTEX Portal (Tissue expression)IER3
Human Protein AtlasENSG00000137331-IER3 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP46695   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP46695  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP46695
Splice isoforms : SwissVarP46695
Domains : Interpro (EBI)IEX-1   
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)IER3
DMDM Disease mutations8870
Blocks (Seattle)IER3
Human Protein Atlas [tissue]ENSG00000137331-IER3 [tissue]
Peptide AtlasP46695
IPIIPI00007831   IPI00025294   IPI00792748   IPI00973565   IPI00554802   
Protein Interaction databases
IntAct (EBI)P46695
Ontologies - Pathways
Ontology : AmiGOprotein binding  nucleus  nucleus  cytosol  apoptotic process  anatomical structure morphogenesis  regulation of phosphatidylinositol 3-kinase signaling  integral component of membrane  negative regulation of apoptotic process  regulation of response to DNA damage stimulus  regulation of response to DNA damage stimulus  
Ontology : EGO-EBIprotein binding  nucleus  nucleus  cytosol  apoptotic process  anatomical structure morphogenesis  regulation of phosphatidylinositol 3-kinase signaling  integral component of membrane  negative regulation of apoptotic process  regulation of response to DNA damage stimulus  regulation of response to DNA damage stimulus  
REACTOMEP46695 [protein]
REACTOME PathwaysR-HSA-6811558 [pathway]   
NDEx NetworkIER3
Atlas of Cancer Signalling NetworkIER3
Wikipedia pathwaysIER3
Orthology - Evolution
GeneTree (enSembl)ENSG00000137331
Phylogenetic Trees/Animal Genes : TreeFamIER3
Homologs : HomoloGeneIER3
Homology/Alignments : Family Browser (UCSC)IER3
Gene fusions - Rearrangements
Fusion : Fusion_HubACBD4--IER3    AMPD3--IER3    ATP6V0A1--IER3    EXT2--IER3    SLC39A7--IER3    TYW1--IER3   
Fusion : QuiverIER3
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerIER3 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)IER3
Exome Variant ServerIER3
GNOMAD BrowserENSG00000137331
Varsome BrowserIER3
Genetic variants : HAPMAP8870
Genomic Variants (DGV)IER3 [DGVbeta]
DECIPHERIER3 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisIER3 
ICGC Data PortalIER3 
TCGA Data PortalIER3 
Broad Tumor PortalIER3
OASIS PortalIER3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICIER3  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DIER3
Mutations and Diseases : HGMDIER3
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch IER3
DgiDB (Drug Gene Interaction Database)IER3
DoCM (Curated mutations)IER3 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)IER3 (select a term)
NCG6 (London) select IER3
Cancer3DIER3(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry IER3
NextProtP46695 [Medical]
Target ValidationIER3
Huge Navigator IER3 [HugePedia]
snp3D : Map Gene to Disease8870
BioCentury BCIQIER3
Clinical trials, drugs, therapy
Protein Interactions : CTD8870
Pharm GKB GenePA29639
Clinical trialIER3
canSAR (ICR)IER3 (select the gene name)
DataMed IndexIER3
PubMed75 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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