ATF4 activating transcription factor 4 [Homo sapiens (human)] - Gene

Summary

Official Symbol: ATF4provided by HGNC
Official Full Name: activating transcription factor 4provided by HGNC
Primary source: HGNC:HGNC:786
See related: Ensembl:ENSG00000128272 MIM:604064; AllianceGenome:HGNC:786
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: CREB2; TXREB; CREB-2; TAXREB67
Summary: This gene encodes a transcription factor that was originally identified as a widely expressed mammalian DNA binding protein that could bind a tax-responsive enhancer element in the LTR of HTLV-1. The encoded protein was also isolated and characterized as the cAMP-response element binding protein 2 (CREB-2). The protein encoded by this gene belongs to a family of DNA-binding proteins that includes the AP-1 family of transcription factors, cAMP-response element binding proteins (CREBs) and CREB-like proteins. These transcription factors share a leucine zipper region that is involved in protein-protein interactions, located C-terminal to a stretch of basic amino acids that functions as a DNA binding domain. Two alternative transcripts encoding the same protein have been described. Two pseudogenes are located on the X chromosome at q28 in a region containing a large inverted duplication. [provided by RefSeq, Sep 2011]
Expression: Ubiquitous expression in bone marrow (RPKM 183.9), fat (RPKM 87.6) and 25 other tissues See more
Orthologs: all
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Try the new Transcripts and proteins table

Genomic context

Location:: 22q13.1

Exon count:: 3

Annotation release	Status	Assembly	Chr	Location
RS_2025_08	current	GRCh38.p14 (GCF_000001405.40)	22	NC_000022.11 (39520559..39522686)
RS_2025_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	22	NC_060946.1 (39985692..39993317)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	22	NC_000022.10 (39916564..39918691)

Chromosome 22 - NC_000022.11 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: Tissue-specific circular RNA induction during human fetal development
Description: 35 human fetal samples from 6 tissues (3 - 7 replicates per tissue) collected between 10 and 20 weeks gestational time were sequenced using Illumina TruSeq Stranded Total RNA
BioProject: PRJNA270632
Publication: PMID 26076956
Analysis date: Mon Apr 2 22:54:59 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

DNA methylation-driven gene FAM3D promotes colorectal cancer growth via the ATF4-SESN2-mTORC1 pathway.
Title: DNA methylation-driven gene FAM3D promotes colorectal cancer growth via the ATF4-SESN2-mTORC1 pathway.
Hyperactivation of ATF4/TGF-beta1 signaling contributes to the progressive cardiac fibrosis in Arrhythmogenic cardiomyopathy caused by DSG2 Variant.
Title: Hyperactivation of ATF4/TGF-β1 signaling contributes to the progressive cardiac fibrosis in Arrhythmogenic cardiomyopathy caused by DSG2 Variant.
Switch of ELF3 and ATF4 transcriptional axis programs the amino acid insufficiency-linked epithelial-to-mesenchymal transition.
Title: Switch of ELF3 and ATF4 transcriptional axis programs the amino acid insufficiency-linked epithelial-to-mesenchymal transition.
Signal Transducer and Activator of Transcription 4-Induced Up-Regulated LINC01278 Enhances Proliferation and Invasion of Non-Small Cell Lung Cancer Cells via the MicroRNA-877-5p/Activating Transcription Factor 4 Axis.
Title: Signal Transducer and Activator of Transcription 4-Induced Up-Regulated LINC01278 Enhances Proliferation and Invasion of Non-Small Cell Lung Cancer Cells via the MicroRNA-877-5p/Activating Transcription Factor 4 Axis.
Novel insights into the activating transcription factor 4 in Alzheimer's disease and associated aging-related diseases: Mechanisms and therapeutic implications.
Title: Novel insights into the activating transcription factor 4 in Alzheimer's disease and associated aging-related diseases: Mechanisms and therapeutic implications.
PTX promotes breast cancer migration and invasion by recruiting ATF4 to upregulate FGF19.
Title: PTX promotes breast cancer migration and invasion by recruiting ATF4 to upregulate FGF19.
Identification of a novel RNA transcript TISPL upregulated by stressors that stimulate ATF4.
Title: Identification of a novel RNA transcript TISPL upregulated by stressors that stimulate ATF4.
ATF4 inhibits tumor development and mediates p-GCN2/ASNS upregulation in colon cancer.
Title: ATF4 inhibits tumor development and mediates p-GCN2/ASNS upregulation in colon cancer.
Stem-loop-induced ribosome queuing in the uORF2/ATF4 overlap fine-tunes stress-induced human ATF4 translational control.
Title: Stem-loop-induced ribosome queuing in the uORF2/ATF4 overlap fine-tunes stress-induced human ATF4 translational control.
miR-214 aggravates oxidative stress in thalassemic erythroid cells by targeting ATF4.
Title: miR-214 aggravates oxidative stress in thalassemic erythroid cells by targeting ATF4.

Submit: New GeneRIF Correction See all GeneRIFs (266)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

EBI GWAS Catalog

Description
Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Protein	Gene	Interaction	Pubs
Tat	tat	HIV-1 infection-mediated upregulation of ATF4 enhances HIV replication by synergistic interaction with HIV Tat	PubMed
	tat	ATF4 enhances HIV-1 LTR activation and induces HIV-1 reactivation in latently infected cells	PubMed
Vpu	vpu	HIV-1 Vpu is a strong competitive inhibitor of beta-TrCP and impairs the degradation of SCF-beta-TrCP substrates such as IKBalpha, ATF4 and beta-catenin	PubMed

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

RH79684 (e-PCR)
- UniSTS:89866

RH71390 (e-PCR)
- UniSTS:14034

PMC166200P2 (e-PCR)
- UniSTS:271574

RH48164 (e-PCR)
- UniSTS:52475

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables DNA binding	IDA Inferred from Direct Assay more info	PubMed
enables DNA binding	IEA Inferred from Electronic Annotation more info
enables DNA binding	ISS Inferred from Sequence or Structural Similarity more info
enables DNA-binding transcription activator activity, RNA polymerase II-specific	IBA Inferred from Biological aspect of Ancestor more info
enables DNA-binding transcription activator activity, RNA polymerase II-specific	IEA Inferred from Electronic Annotation more info
enables DNA-binding transcription factor activity	IDA Inferred from Direct Assay more info	PubMed
enables DNA-binding transcription factor activity	IEA Inferred from Electronic Annotation more info
enables DNA-binding transcription factor activity	TAS Traceable Author Statement more info	PubMed
enables DNA-binding transcription factor activity, RNA polymerase II-specific	IDA Inferred from Direct Assay more info	PubMed
contributes_to DNA-binding transcription factor activity, RNA polymerase II-specific	IEA Inferred from Electronic Annotation more info
enables DNA-binding transcription factor activity, RNA polymerase II-specific	ISA Inferred from Sequence Alignment more info
enables DNA-binding transcription factor binding	IEA Inferred from Electronic Annotation more info
contributes_to RNA polymerase II cis-regulatory region sequence-specific DNA binding	IEA Inferred from Electronic Annotation more info
enables RNA polymerase II cis-regulatory region sequence-specific DNA binding	ISS Inferred from Sequence or Structural Similarity more info
enables RNA polymerase II transcription regulatory region sequence-specific DNA binding	IBA Inferred from Biological aspect of Ancestor more info
enables RNA polymerase II-specific DNA-binding transcription factor binding	IPI Inferred from Physical Interaction more info	PubMed
enables cAMP response element binding	IEA Inferred from Electronic Annotation more info
enables cAMP response element binding protein binding	IEA Inferred from Electronic Annotation more info
enables cAMP response element binding protein binding	ISS Inferred from Sequence or Structural Similarity more info
enables general transcription initiation factor binding	IEA Inferred from Electronic Annotation more info
enables identical protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables leucine zipper domain binding	IDA Inferred from Direct Assay more info	PubMed
enables promoter-specific chromatin binding	IDA Inferred from Direct Assay more info	PubMed
enables promoter-specific chromatin binding	IEA Inferred from Electronic Annotation more info
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein heterodimerization activity	IEA Inferred from Electronic Annotation more info
enables protein heterodimerization activity	ISS Inferred from Sequence or Structural Similarity more info
enables protein kinase binding	IPI Inferred from Physical Interaction more info	PubMed
enables sequence-specific DNA binding	IDA Inferred from Direct Assay more info	PubMed
enables sequence-specific double-stranded DNA binding	IDA Inferred from Direct Assay more info	PubMed
contributes_to transcription cis-regulatory region binding	IDA Inferred from Direct Assay more info	PubMed
enables transcription cis-regulatory region binding	IDA Inferred from Direct Assay more info	PubMed
enables transcription cis-regulatory region binding	TAS Traceable Author Statement more info	PubMed

Process	Evidence Code	Pubs
involved_in HRI-mediated signaling	IDA Inferred from Direct Assay more info	PubMed
involved_in L-asparagine metabolic process	IDA Inferred from Direct Assay more info	PubMed
involved_in PERK-mediated unfolded protein response	IDA Inferred from Direct Assay more info	PubMed
involved_in PERK-mediated unfolded protein response	IEA Inferred from Electronic Annotation more info
involved_in PERK-mediated unfolded protein response	ISS Inferred from Sequence or Structural Similarity more info
involved_in PERK-mediated unfolded protein response	TAS Traceable Author Statement more info	PubMed
involved_in bone mineralization	IEA Inferred from Electronic Annotation more info
involved_in bone mineralization	ISS Inferred from Sequence or Structural Similarity more info
involved_in cellular response to UV	ISS Inferred from Sequence or Structural Similarity more info
involved_in cellular response to amino acid starvation	IEA Inferred from Electronic Annotation more info
involved_in cellular response to amino acid starvation	ISS Inferred from Sequence or Structural Similarity more info
involved_in cellular response to glucose starvation	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in cellular response to hypoxia	IEA Inferred from Electronic Annotation more info
involved_in cellular response to leucine starvation	IDA Inferred from Direct Assay more info	PubMed
involved_in cellular response to leucine starvation	IEA Inferred from Electronic Annotation more info
involved_in cellular response to oxidative stress	IEA Inferred from Electronic Annotation more info
involved_in cellular response to oxidative stress	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in cellular response to oxidative stress	ISS Inferred from Sequence or Structural Similarity more info
involved_in circadian regulation of gene expression	IEA Inferred from Electronic Annotation more info
involved_in circadian regulation of gene expression	ISS Inferred from Sequence or Structural Similarity more info
involved_in circadian rhythm	IEA Inferred from Electronic Annotation more info
involved_in embryonic hemopoiesis	IEA Inferred from Electronic Annotation more info
involved_in embryonic hemopoiesis	ISS Inferred from Sequence or Structural Similarity more info
involved_in endoplasmic reticulum unfolded protein response	IEA Inferred from Electronic Annotation more info
involved_in endoplasmic reticulum unfolded protein response	ISS Inferred from Sequence or Structural Similarity more info
involved_in gamma-aminobutyric acid signaling pathway	IEA Inferred from Electronic Annotation more info
involved_in gluconeogenesis	ISS Inferred from Sequence or Structural Similarity more info
involved_in integrated stress response signaling	IDA Inferred from Direct Assay more info	PubMed
involved_in integrated stress response signaling	IEA Inferred from Electronic Annotation more info
involved_in integrated stress response signaling	NAS Non-traceable Author Statement more info	PubMed
involved_in intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	IEA Inferred from Electronic Annotation more info
involved_in intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	ISS Inferred from Sequence or Structural Similarity more info
involved_in lens fiber cell morphogenesis	IEA Inferred from Electronic Annotation more info
involved_in lens fiber cell morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
involved_in mRNA transcription by RNA polymerase II	IEA Inferred from Electronic Annotation more info
involved_in mRNA transcription by RNA polymerase II	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of cold-induced thermogenesis	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of cold-induced thermogenesis	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway	IGI Inferred from Genetic Interaction more info	PubMed
involved_in negative regulation of potassium ion transport	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of transcription by RNA polymerase II	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of transcription by RNA polymerase II	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of translational initiation in response to stress	ISS Inferred from Sequence or Structural Similarity more info
involved_in neuron differentiation	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of DNA-templated transcription	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of DNA-templated transcription	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of DNA-templated transcription	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of DNA-templated transcription	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of DNA-templated transcription	NAS Non-traceable Author Statement more info	PubMed
involved_in positive regulation of apoptotic process	TAS Traceable Author Statement more info	PubMed
involved_in positive regulation of gene expression	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of gene expression	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of neuron apoptotic process	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of neuron apoptotic process	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of transcription by RNA polymerase I	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of transcription by RNA polymerase II	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of transcription by RNA polymerase II	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of transcription by RNA polymerase II	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of transcription by RNA polymerase II	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in positive regulation of transcription by RNA polymerase II	TAS Traceable Author Statement more info	PubMed
involved_in positive regulation of vascular endothelial growth factor production	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of DNA-templated transcription	IEA Inferred from Electronic Annotation more info
involved_in regulation of DNA-templated transcription	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of apoptotic process	IEA Inferred from Electronic Annotation more info
involved_in regulation of osteoblast differentiation	IDA Inferred from Direct Assay more info	PubMed
involved_in regulation of osteoblast differentiation	IEA Inferred from Electronic Annotation more info
involved_in regulation of synaptic plasticity	IEA Inferred from Electronic Annotation more info
involved_in regulation of synaptic plasticity	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of transcription by RNA polymerase II	IBA Inferred from Biological aspect of Ancestor more info
involved_in regulation of transcription by RNA polymerase II	NAS Non-traceable Author Statement more info	PubMed
involved_in response to endoplasmic reticulum stress	IDA Inferred from Direct Assay more info	PubMed
involved_in response to endoplasmic reticulum stress	IEA Inferred from Electronic Annotation more info
involved_in response to endoplasmic reticulum stress	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in response to manganese-induced endoplasmic reticulum stress	IEA Inferred from Electronic Annotation more info
involved_in response to nutrient levels	IDA Inferred from Direct Assay more info	PubMed
involved_in response to toxic substance	IEA Inferred from Electronic Annotation more info
involved_in rhythmic process	IEA Inferred from Electronic Annotation more info
involved_in transcription by RNA polymerase II	ISS Inferred from Sequence or Structural Similarity more info

Component	Evidence Code	Pubs
part_of ATF1-ATF4 transcription factor complex	IBA Inferred from Biological aspect of Ancestor more info
part_of ATF1-ATF4 transcription factor complex	IDA Inferred from Direct Assay more info	PubMed
part_of ATF1-ATF4 transcription factor complex	IEA Inferred from Electronic Annotation more info
part_of ATF4-CREB1 transcription factor complex	IBA Inferred from Biological aspect of Ancestor more info
part_of ATF4-CREB1 transcription factor complex	IDA Inferred from Direct Assay more info	PubMed
part_of ATF4-CREB1 transcription factor complex	IEA Inferred from Electronic Annotation more info
part_of CHOP-ATF4 complex	IDA Inferred from Direct Assay more info	PubMed
part_of CHOP-ATF4 complex	IPI Inferred from Physical Interaction more info	PubMed
part_of CHOP-ATF4 complex	NAS Non-traceable Author Statement more info	PubMed
located_in Lewy body core	IDA Inferred from Direct Assay more info	PubMed
part_of RNA polymerase II transcription regulator complex	IEA Inferred from Electronic Annotation more info
colocalizes_with centrosome	IDA Inferred from Direct Assay more info	PubMed
located_in centrosome	IEA Inferred from Electronic Annotation more info
located_in chromatin	ISA Inferred from Sequence Alignment more info
located_in cytoplasm	IDA Inferred from Direct Assay more info	PubMed
located_in cytoplasm	IEA Inferred from Electronic Annotation more info
located_in cytoplasm	ISS Inferred from Sequence or Structural Similarity more info
located_in cytosol	TAS Traceable Author Statement more info
located_in dendrite membrane	IEA Inferred from Electronic Annotation more info
located_in neuron projection	IDA Inferred from Direct Assay more info	PubMed
located_in nuclear periphery	IDA Inferred from Direct Assay more info	PubMed
located_in nuclear speck	IEA Inferred from Electronic Annotation more info
located_in nucleoplasm	IDA Inferred from Direct Assay more info
located_in nucleoplasm	TAS Traceable Author Statement more info
is_active_in nucleus	IBA Inferred from Biological aspect of Ancestor more info
located_in nucleus	IDA Inferred from Direct Assay more info	PubMed
located_in nucleus	IEA Inferred from Electronic Annotation more info
located_in nucleus	ISS Inferred from Sequence or Structural Similarity more info
located_in nucleus	NAS Non-traceable Author Statement more info	PubMed
located_in plasma membrane	IEA Inferred from Electronic Annotation more info
part_of protein-containing complex	IDA Inferred from Direct Assay more info	PubMed
part_of transcription regulator complex	IEA Inferred from Electronic Annotation more info

General protein information

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Preferred Names: cyclic AMP-dependent transcription factor ATF-4

Names: DNA-binding protein TAXREB67; cAMP response element-binding protein 2; cAMP-dependent transcription factor ATF-4; cAMP-responsive element-binding protein 2; cyclic AMP-responsive element-binding protein 2; tax-responsive enhancer element B67; tax-responsive enhancer element-binding protein 67

NCBI Reference Sequences (RefSeq)

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NEW Try the new Transcript table

RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

mRNA and Protein(s)

NM_001675.4 → NP_001666.2 cyclic AMP-dependent transcription factor ATF-4

See identical proteins and their annotated locations for NP_001666.2

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the longer transcript. The protein translation of this variant is regulated by an internal ribosome entry site (PMID: 23665047). Both variants 1 and 2 encode the same protein.

Source sequence(s)

AL022312, BC011994, D90209

Consensus CDS

CCDS13996.1

UniProtKB/Swiss-Prot

P18848, Q96AQ3, Q9UH31

UniProtKB/TrEMBL

Q6ICP0

Related

ENSP00000336790.2, ENST00000337304.2

Conserved Domains (1) summary

cd14692
Location:279 → 341

bZIP_ATF4; Basic leucine zipper (bZIP) domain of Activating Transcription Factor-4 (ATF-4) and similar proteins: a DNA-binding and dimerization domain
NM_182810.3 → NP_877962.1 cyclic AMP-dependent transcription factor ATF-4

See identical proteins and their annotated locations for NP_877962.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) lacks an internal segment in the 5' UTR, compared to variant 1. The protein translation of this variant is regulated by two upstream open reading frames (PMID: 15277680). Both variants 1 and 2 encode the same protein.

Source sequence(s)

AL022312

Consensus CDS

CCDS13996.1

UniProtKB/Swiss-Prot

P18848, Q96AQ3, Q9UH31

UniProtKB/TrEMBL

Q6ICP0

Related

ENSP00000501863.1, ENST00000674920.3

Conserved Domains (1) summary

cd14692
Location:279 → 341

bZIP_ATF4; Basic leucine zipper (bZIP) domain of Activating Transcription Factor-4 (ATF-4) and similar proteins: a DNA-binding and dimerization domain

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2025_08

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

NC_000022.11 Reference GRCh38.p14 Primary Assembly

Range

39520559..39522686

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate T2T-CHM13v2.0

Genomic

NC_060946.1 Alternate T2T-CHM13v2.0

Range

39985692..39993317

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_054325649.1 → XP_054181624.1 cyclic AMP-dependent transcription factor ATF-4 isoform X1

UniProtKB/TrEMBL

Q6ICP0
XM_054325650.1 → XP_054181625.1 cyclic AMP-dependent transcription factor ATF-4 isoform X1

UniProtKB/TrEMBL

Q6ICP0