IER3 (immediate early response 3)

2009-12-01   Heiner Schäfer , Alexander Arlt 

1st Department of Medicine, UKSH Campus Kiel, Schittenhelmstr. 12, 24105 Kiel, Germany


Atlas Image


Atlas Image
The IER3 pre-mRNA contains two exons and one intron (112 bp). cds: coding strand; 5UTR: 5untranslated region; 3UTR: 3untranslated region, ARE: A-rich element.


The IER3 gene spans 1351 bp genomic DNA and consists of 2 coding exons. The coding sequence of IER3 is 498 nucleotides long.


Atlas Image
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).


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).


Epithelial cells, keratinocytes, hepatocytes, monocytes, lymphocytes.


Nucleus, mitochondrial membrane, cytoplasm.


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.





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).
Atlas Image
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 name
Colon cancer
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 name
Pancreatic cancer
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 name
Multiple Endocrine Neoplasia type 1 (MEN1) tumors
IER3 expression is inversely related to the formation of endocrine tumors (Dilley et al., 2005).


Pubmed IDLast YearTitleAuthors
112445052001Expression 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 et al
127615042003The early response gene IEX-1 attenuates NF-kappaB activation in 293 cells, a possible counter-regulatory process leading to enhanced cell death.Arlt A et al
171073442007Immediate 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 et al
181916422008IEX-1 directly interferes with RelA/p65 dependent transactivation and regulation of apoptosis.Arlt A et al
156913812005Global gene expression in neuroendocrine tumors from patients with the MEN1 syndrome.Dilley WG et al
123567312002IEX-1: a new ERK substrate involved in both ERK survival activity and ERK activation.Garcia J et al
86033921996Identification and characterization of a radiation-inducible glycosylated human early-response gene.Kondratyev AD et al
158551592005Immediate early gene X1 (IEX-1) is organized in subnuclear structures and partially co-localizes with promyelocytic leukemia protein in HeLa cells.Kruse ML et al
164559742006NF-kappaB-dependent regulation of the timing of activation-induced cell death of T lymphocytes.Mittal A et al
153749462004Genetic signatures of high- and low-risk aberrant crypt foci in a mouse model of sporadic colon cancer.Nambiar PR et al
172001152007Inhibition of B56-containing protein phosphatase 2As by the early response gene IEX-1 leads to control of Akt activity.Rocher G et al
180267992008Prognostic significance of the immediate early response gene X-1 (IEX-1) expression in pancreatic cancer.Sasada T et al
104480821999The putative apoptosis inhibitor IEX-1L is a mutant nonspliced variant of p22(PRG1/IEX-1) and is not expressed in vivo.Schäfer H et al
86537101996PRG1: a novel early-response gene transcriptionally induced by pituitary adenylate cyclase activating polypeptide in a pancreatic carcinoma cell line.Schäfer H et al
117536822001IEX-1, an immediate early gene, increases the rate of apoptosis in keratinocytes.Schilling D et al
177048042008The apoptosis-inducing effect of gastrin on colorectal cancer cells relates to an increased IEX-1 expression mediating NF-kappa B inhibition.Sebens Müerköster S et al
190963922009IEX-1 targets mitochondrial F1Fo-ATPase inhibitor for degradation.Shen L et al
97035171998IEX-1L, an apoptosis inhibitor involved in NF-kappaB-mediated cell survival.Wu MX et al
125101472003Roles of the stress-induced gene IEX-1 in regulation of cell death and oncogenesis.Wu MX et al

Other Information

Locus ID:

NCBI: 8870
MIM: 602996
HGNC: 5392
Ensembl: ENSG00000137331


dbSNP: 8870
ClinVar: 8870
TCGA: ENSG00000137331


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
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
Negative regulation of the PI3K/AKT networkREACTOMER-HSA-199418
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
PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingREACTOMER-HSA-6811558

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
198514452009High-density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions.51
211121192011Role of the immediate early response 3 (IER3) gene in cellular stress response, inflammation and tumorigenesis.49
125101472003Roles of the stress-induced gene IEX-1 in regulation of cell death and oncogenesis.38
196901922009Gene expression profiling of bone marrow endothelial cells in patients with multiple myeloma.36
123567312002IEX-1: a new ERK substrate involved in both ERK survival activity and ERK activation.31
117825302002Impaired apoptosis, extended duration of immune responses, and a lupus-like autoimmune disease in IEX-1-transgenic mice.29
127432742003The stress-inducible immediate-early responsive gene IEX-1 is activated in cells infected with herpes simplex virus 1, but several viral mechanisms, including 3' degradation of its RNA, preclude expression of the gene.28
165678052006Distinct domains for anti- and pro-apoptotic activities of IEX-1.22
169735762006Herpes simplex virus ICP27 is required for virus-induced stabilization of the ARE-containing IEX-1 mRNA encoded by the human IER3 gene.20
157816302005p73beta-Mediated apoptosis requires p57kip2 induction and IEX-1 inhibition.18


Heiner Schäfer ; Alexander Arlt

IER3 (immediate early response 3)

Atlas Genet Cytogenet Oncol Haematol. 2009-12-01

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