IER5

Summary

IER5 (immediate early response 5, HGNC:5393) is a protein-coding gene on chromosome 1q25.3, encoding Immediate early response gene 5 protein (Q5VY09). Plays a role as a transcription factor.

This gene encodes a protein that is similar to other immediate early response proteins. In the mouse, a similar gene may play an important role in mediating the cellular response to mitogenic signals. Studies in rats found the expression of a similar gene to be increased after waking and sleep deprivation.

Source: NCBI Gene 51278 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 59 total
• MANE Select transcript: NM_016545

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5393
Approved symbol	IER5
Name	immediate early response 5
Location	1q25.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000162783
Ensembl biotype	protein_coding
OMIM	607177
Entrez	51278

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000367577

RefSeq mRNA: 1 — MANE Select: NM_016545 NM_016545

CCDS: CCDS1343

Canonical transcript exons

ENST00000367577 — 1 exons

Exon	Start	End
ENSE00001445067	181088700	181092900

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 98.36.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 57.1411 / max 1610.2672, expressed in 1821 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
6984	56.5128	1821
6985	0.4344	204
6983	0.1938	34

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
amniotic fluid	UBERON:0000173	98.36	gold quality
palpebral conjunctiva	UBERON:0001812	97.79	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.35	gold quality
lower lobe of lung	UBERON:0008949	97.15	gold quality
penis	UBERON:0000989	96.88	gold quality
epithelium of nasopharynx	UBERON:0001951	96.80	gold quality
mucosa of urinary bladder	UBERON:0001259	96.72	gold quality
pharyngeal mucosa	UBERON:0000355	96.59	gold quality
trachea	UBERON:0003126	96.47	gold quality
epithelium of esophagus	UBERON:0001976	96.34	gold quality
nipple	UBERON:0002030	96.30	gold quality
oral cavity	UBERON:0000167	96.28	gold quality
esophagus squamous epithelium	UBERON:0006920	96.25	gold quality
cartilage tissue	UBERON:0002418	96.14	gold quality
squamous epithelium	UBERON:0006914	95.55	gold quality
body of tongue	UBERON:0011876	95.54	gold quality
gingival epithelium	UBERON:0001949	95.42	gold quality
mononuclear cell	CL:0000842	95.37	gold quality
monocyte	CL:0000576	95.35	gold quality
upper leg skin	UBERON:0004262	95.31	gold quality
tongue	UBERON:0001723	95.29	gold quality
vena cava	UBERON:0004087	95.24	gold quality
gingiva	UBERON:0001828	95.18	gold quality
mammary duct	UBERON:0001765	94.99	gold quality
superior surface of tongue	UBERON:0007371	94.99	gold quality
leukocyte	CL:0000738	94.94	gold quality
epithelium of mammary gland	UBERON:0003244	94.70	gold quality
mucosa of paranasal sinus	UBERON:0005030	94.65	gold quality
superficial temporal artery	UBERON:0001614	94.52	gold quality
tibialis anterior	UBERON:0001385	94.39	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-79	yes	1286.59
E-HCAD-13	yes	7.40
E-GEOD-110499	no	320.75
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ETS1, JUN, NFYB

miRNA regulators (miRDB)

78 targeting IER5, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-3180-5P	99.82	69.12	2422

Literature-anchored findings (GeneRIF, showing 14)

• Studies in rat found higher mRNA levels after waking and sleep deprivation for immediate early genes/transcription factors such as IER5 (PMID:11102586)
• the early radiation-induced expression of IER5 affects radiosensitivity via disturbing radiation-induced cell cycle checkpoints (PMID:19238419)
• Transcriptional repression mediated by IER5 regulates Cdc25B expression levels via the release of NF-YB and p300 in acute myeloid leukemia. (PMID:22132193)
• These observations suggest that HSF1-mediated IER5 expression is involved in the expression of chaperone genes and in recovery from thermal stress. (PMID:25355627)
• IER5 functions as a positive feedback regulator of HSF1 and that this process involves PP2A/B55 and HSF1 dephosphorylation. (PMID:25816751)
• These results reveal the existence of a novel IER5-mediated cancer regulation pathway that is responsible for the activation of HSF1 observed in various cancers. (PMID:26754925)
• Authors propose the GCF regulated transcriptional activity, at least in part, contributed to the upregulation of IER5 on radiation in HepG2 cells. The present findings provide insights into understanding the regulatory mechanisms of IER5. (PMID:26915404)
• we confirmed that IER5 induced by radiation dose enhanced apoptosis of cervical cancer, was inversely associated with tumor size. (PMID:28430589)
• Observations suggest that IER5 is a novel regulator of the non-homologous end-joining pathway pathway for DNA double-strand breaks repair, possibly through its interaction with PARP1 and Ku70. (PMID:29104487)
• The results suggest that IER2, IER5, and IER5L proteins are target protein-specific regulators of PP2A (protein phosphatase 2A) activity and modulate cell proliferation through CDC25A (cell division cycle 25A protein) activity. (PMID:30599213)
• Nuclear localization signal at amino acids 217-244 mediates complex formation with importin-alpha and importin-beta. NLS is essential for HSF1 dephosphorylation and full activation by IER5. (PMID:31669744)
• Novel role of PAF1 in attenuating radiosensitivity in cervical cancer by inhibiting IER5 transcription. (PMID:32471508)
• IER5, a DNA damage response gene, is required for Notch-mediated induction of squamous cell differentiation. (PMID:32936072)
• PP2A-B55 and its adapter proteins IER2 and IER5 regulate the activity of RB family proteins and the expression of cell cycle-related genes. (PMID:36047562)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio	ier5	ENSDARG00000009881
mus_musculus	Ier5	ENSMUSG00000056708

Paralogs (2): IER2 (ENSG00000160888), IER5L (ENSG00000188483)

Protein

Protein identifiers

Immediate early response gene 5 protein — Q5VY09 (reviewed: Q5VY09)

All UniProt accessions (1): Q5VY09

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role as a transcription factor. Mediates positive transcriptional regulation of several chaperone genes during the heat shock response in a HSF1-dependent manner. Mediates negative transcriptional regulation of CDC25B expression. Plays a role in the dephosphorylation of the heat shock factor HSF1 and ribosomal protein S6 kinase (S6K) by the protein phosphatase PP2A. Involved in the regulation of cell proliferation and resistance to thermal stress. Involved in the cell cycle checkpoint and survival in response to ionizing radiation. Associates with chromatin to the CDC25B promoter.

Subunit / interactions. Monomer. Homodimer. Associates with the catalytic subunit of protein phosphatase PP2A. Interacts (via N- and C-terminal regions) with PPP2R2B. Interacts with PPP2R2A, PPP2R2C and PPP2R2D. Interacts (via N-terminus) with RPS6KB1. Interacts (via central region) with HSF1; this interaction promotes PPP2CA-induced HSF1 dephosphorylation, leading to enhanced HSF1 transcriptional activity.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Expressed in acute myeloid leukemia (AML) cells.

Induction. Up-regulated by heat shock in a heat shock HSF1-dependent manner. Up-regulated by ionizing radiation.

Similarity. Belongs to the IER family.

RefSeq proteins (1): NP_057629* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008653	IER	Family

Pfam: PF05760

UniProt features (12 total): sequence variant 5, compositionally biased region 3, region of interest 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8UO5	ELECTRON MICROSCOPY	3.27

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5VY09-F1	54.22	0.07

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 340 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE45365_NK_CELL_VS_CD11B_DC_DN, GSE45365_NK_CELL_VS_BCELL_UP, AGGAAGC_MIR5163P, CREL_01, CMYB_01, TTTGTAG_MIR520D, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, ADDYA_ERYTHROID_DIFFERENTIATION_BY_HEMIN, NAGASHIMA_NRG1_SIGNALING_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_HEAT, NFKB_Q6, NFKB_C, CHEN_LVAD_SUPPORT_OF_FAILING_HEART_UP

GO Biological Process (4): cellular response to heat (GO:0034605), regulation of cell population proliferation (GO:0042127), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of cellular response to heat (GO:1900036)

GO Molecular Function (2): identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), protein phosphatase type 2A complex (GO:0000159)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nuclear lumen	2
cellular anatomical structure	2
response to heat	1
cellular response to stress	1
cell population proliferation	1
regulation of cellular process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
cellular response to heat	1
positive regulation of cellular process	1
positive regulation of response to stimulus	1
regulation of cellular response to heat	1
protein binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
protein serine/threonine phosphatase complex	1

Protein interactions and networks

STRING

706 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IER5	MPDZ	O75970	765
IER5	PDZK1IP1	Q13113	589
IER5	MYCL	P12524	543
IER5	TAL1	P17542	497
IER5	TAL2	Q16559	496
IER5	ETS1	P14921	495
IER5	C1QBP	Q07021	469
IER5	STX6	O43752	443
IER5	BTG2	P78543	405
IER5	H0Y8G9	H0Y8G9	396
IER5	ANKRD34C	P0C6C1	394
IER5	HERC3	Q15034	394
IER5	KIRREL1	Q96J84	391
IER5	GADD45A	P24522	387
IER5	PHLDA3	Q9Y5J5	385

IntAct

33 interactions, top by confidence:

A	B	Type	Score
PPP2R1A	STRN	psi-mi:“MI:0914”(association)	0.880
PPP2R2D	YEATS4	psi-mi:“MI:0914”(association)	0.730
PPP2R2C	PPP2R1A	psi-mi:“MI:0914”(association)	0.730
PPP2R2B	MYO9A	psi-mi:“MI:0914”(association)	0.640
HSF1	IER5	psi-mi:“MI:0915”(physical association)	0.590
IER5	HSF1	psi-mi:“MI:0915”(physical association)	0.590
PPP2R2D	ENSA	psi-mi:“MI:0914”(association)	0.570
PPP2R1A	ENSA	psi-mi:“MI:0914”(association)	0.530
MINK1	IER5	psi-mi:“MI:0407”(direct interaction)	0.440
PPP2R2B	TCP1	psi-mi:“MI:0914”(association)	0.420
IER5	IER5	psi-mi:“MI:0915”(physical association)	0.400
IER5	MINK1	psi-mi:“MI:0915”(physical association)	0.400
IER5	PPP2CA	psi-mi:“MI:0915”(physical association)	0.400
IER5	RPS6KB1	psi-mi:“MI:0915”(physical association)	0.400
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
PPP2R2A	ENSA	psi-mi:“MI:0914”(association)	0.350
PPP2R2C	IER5	psi-mi:“MI:0914”(association)	0.350
PPP2R2C	TCP1	psi-mi:“MI:0914”(association)	0.350
PPP2R2B	A2ML1	psi-mi:“MI:0914”(association)	0.350
PPP2R2B	ARHGAP10	psi-mi:“MI:0914”(association)	0.350

BioGRID (21): IER5 (Affinity Capture-MS), IER5 (Affinity Capture-MS), IER5 (Affinity Capture-MS), IER5 (Affinity Capture-MS), IER5 (Affinity Capture-MS), IER5 (Affinity Capture-MS), IER5 (Affinity Capture-MS), IER5 (Affinity Capture-MS), IER5 (Affinity Capture-MS), IER5 (Affinity Capture-RNA), IER5 (Affinity Capture-MS), IER5 (Affinity Capture-MS), IER5 (Affinity Capture-MS), IER5 (Affinity Capture-MS), CDC25B (Affinity Capture-Western)

ESM2 similar proteins: A0A1W2PPE3, A0A2R8Y2Y2, A0A494C0N9, A0A494C0Y3, A0A7I2V3R4, A0JNN8, A2VDX9, A5A769, A5PJP1, A6QPM6, A8MTW9, C9JTQ0, O15370, O35182, O43541, O70218, O75474, O89113, O94850, P0C7X2, P0DPE3, P28283, P37318, P37319, P70339, Q04890, Q10586, Q32PF6, Q5BLP8, Q5T230, Q5U5M8, Q5VY09, Q60925, Q6IQX8, Q6NZ36, Q6NZY7, Q6QNY0, Q6ZSJ8, Q7TNS8, Q80WY3

Diamond homologs: B7SXM5, O89113, P17950, Q5PQP0, Q5T953, Q5VY09, Q66IT9, Q6NYT3, Q6P7D3, Q6PBC9, Q99J55, Q9BTL4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

59 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

105 predictions. Top by Δscore:

Variant	Effect	Δscore
1:181088801:A:AG	donor_gain	0.7300
1:181089406:ATCT:A	donor_gain	0.6400
1:181089407:TCTC:T	donor_gain	0.6300
1:181089314:G:GT	donor_gain	0.6200
1:181089553:G:GT	donor_gain	0.5600
1:181088802:T:G	donor_gain	0.5300
1:181089270:C:G	donor_gain	0.5100
1:181089381:G:GT	donor_gain	0.4800
1:181089237:G:A	donor_gain	0.4700
1:181089408:C:G	donor_gain	0.4600
1:181089773:G:GT	donor_gain	0.4600
1:181090609:TCAG:T	donor_gain	0.4600
1:181089374:ACCGC:A	donor_gain	0.4500
1:181089375:CCGCC:C	donor_gain	0.4500
1:181089281:G:T	donor_gain	0.4400
1:181088950:C:T	donor_gain	0.4300
1:181090082:G:GT	donor_gain	0.4300
1:181089121:G:T	donor_gain	0.4100
1:181089244:G:T	donor_gain	0.4100
1:181089281:G:GT	donor_gain	0.4100
1:181088748:T:A	donor_gain	0.4000
1:181088994:A:AG	donor_gain	0.4000
1:181090088:G:GT	donor_gain	0.4000
1:181089020:C:CG	donor_gain	0.3900
1:181089362:G:GT	donor_gain	0.3900
1:181088992:GCA:G	donor_gain	0.3700
1:181089728:A:AG	acceptor_gain	0.3700
1:181089729:G:GG	acceptor_gain	0.3700
1:181088725:G:GT	donor_gain	0.3600
1:181089243:G:GT	donor_gain	0.3600

AlphaMissense

2079 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:181089003:T:C	L34P	1.000
1:181089708:T:C	L269P	1.000
1:181089719:T:C	F273L	1.000
1:181089721:C:A	F273L	1.000
1:181089721:C:G	F273L	1.000
1:181088931:T:A	I10N	0.999
1:181088931:T:G	I10S	0.999
1:181088934:T:A	V11D	0.999
1:181088936:A:C	S12R	0.999
1:181088938:C:A	S12R	0.999
1:181088938:C:G	S12R	0.999
1:181088955:T:C	I18T	0.999
1:181088991:T:C	L30P	0.999
1:181088993:C:G	H31D	0.999
1:181088998:G:C	K32N	0.999
1:181088998:G:T	K32N	0.999
1:181089006:T:C	L35P	0.999
1:181089015:T:C	L38P	0.999
1:181089021:T:C	L40P	0.999
1:181089030:C:A	A43D	0.999
1:181089708:T:A	L269H	0.999
1:181089711:T:A	I270N	0.999
1:181089720:T:C	F273S	0.999
1:181089720:T:G	F273C	0.999
1:181089731:T:C	F277L	0.999
1:181089732:T:C	F277S	0.999
1:181089733:C:A	F277L	0.999
1:181089733:C:G	F277L	0.999
1:181089860:T:A	W320R	0.999
1:181089860:T:C	W320R	0.999

dbSNP variants (sampled 300 via entrez): RS1001032830 (1:181086832 A>T), RS1001106473 (1:181087082 A>G), RS1001332719 (1:181087671 G>A), RS1001659572 (1:181087267 C>T), RS1001700582 (1:181092004 A>G), RS1003594739 (1:181088667 C>G,T), RS1004073474 (1:181088722 G>A,C), RS1005537901 (1:181092389 C>A,T), RS1005605826 (1:181088826 C>G,T), RS1005737705 (1:181089525 C>A,G,T), RS1006068949 (1:181087834 A>G), RS1007059640 (1:181089096 C>A,T), RS1007177384 (1:181093160 CT>C), RS1007396576 (1:181092801 T>C), RS1007398103 (1:181088508 G>A)

Disease associations

OMIM: gene MIM:607177 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST005171_29	QT interval	5.000000e-06
GCST010697_5	Cortical surface area (min-P)	4.000000e-11
GCST010698_73	Subcortical volume (min-P)	1.000000e-13
GCST010699_38	Brain morphology (min-P)	1.000000e-08
GCST010700_67	Cortical thickness (MOSTest)	4.000000e-09
GCST010701_105	Cortical surface area (MOSTest)	3.000000e-12
GCST010702_28	Subcortical volume (MOSTest)	6.000000e-11
GCST010703_252	Brain morphology (MOSTest)	4.000000e-14
GCST90002381_10	Eosinophil count	2.000000e-10
GCST90002382_19	Eosinophil percentage of white cells	2.000000e-10

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

80 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression	7
Aflatoxin B1	affects expression, increases expression	5
trichostatin A	affects cotreatment, increases expression, affects expression	4
cobaltous chloride	increases expression	2
cupric chloride	increases expression	2
Cisplatin	increases expression, increases cleavage, increases reaction	2
Copper	affects binding, decreases expression, increases expression	2
Formaldehyde	increases expression	2
Hydrogen Peroxide	affects expression, increases expression	2
Methyl Methanesulfonate	increases expression	2
Silver	increases expression	2
Tobacco Smoke Pollution	increases expression	2
Tretinoin	decreases expression, increases expression	2
Valproic Acid	increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	decreases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
hydroxyhydroquinone	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
methylparaben	increases expression	1
sodium arsenite	increases expression	1
manganese chloride	increases abundance, increases expression	1
periodate-oxidized adenosine	affects expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	decreases expression, affects cotreatment	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.