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: mouse all
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Genomic context

Location:: 22q13.1

Exon count:: 3

Annotation release	Status	Assembly	Chr	Location
RS_2023_10	current	GRCh38.p14 (GCF_000001405.40)	22	NC_000022.11 (39520559..39522686)
RS_2023_10	current	T2T-CHM13v2.0 (GCF_009914755.1)	22	NC_060946.1 (39985692..39993317)
105.20220307	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: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

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.
Transcriptional regulation of amino acid metabolism by KDM2B, in the context of ncPRC1.1 and in concert with MYC and ATF4.
Title: Transcriptional regulation of amino acid metabolism by KDM2B, in the context of ncPRC1.1 and in concert with MYC and ATF4.
Advanced glycation end products promote meniscal calcification by activating the mTOR-ATF4 positive feedback loop.
Title: Advanced glycation end products promote meniscal calcification by activating the mTOR-ATF4 positive feedback loop.
ATF4 in cellular stress, ferroptosis, and cancer.
Title: ATF4 in cellular stress, ferroptosis, and cancer.
Gut-derived ammonia contributes to alcohol-related fatty liver development via facilitating ethanol metabolism and provoking ATF4-dependent de novo lipogenesis activation.
Title: Gut-derived ammonia contributes to alcohol-related fatty liver development via facilitating ethanol metabolism and provoking ATF4-dependent de novo lipogenesis activation.
Endometrial stromal cell autophagy-dependent ferroptosis caused by iron overload in ovarian endometriosis is inhibited by the ATF4-xCT pathway.
Title: Endometrial stromal cell autophagy-dependent ferroptosis caused by iron overload in ovarian endometriosis is inhibited by the ATF4-xCT pathway.
The ATF4-regulated LncRNA MALAT1 promotes odontoblastic differentiation of human dental pulp stem cells via histone demethylase JMJD3: An in vitro study.
Title: The ATF4-regulated LncRNA MALAT1 promotes odontoblastic differentiation of human dental pulp stem cells via histone demethylase JMJD3: An in vitro study.
Genome-wide census of ATF4 binding sites and functional profiling of trait-associated genetic variants overlapping ATF4 binding motifs.
Title: Genome-wide census of ATF4 binding sites and functional profiling of trait-associated genetic variants overlapping ATF4 binding motifs.
YAP governs cellular adaptation to perturbation of glutamine metabolism by regulating ATF4-mediated stress response.
Title: YAP governs cellular adaptation to perturbation of glutamine metabolism by regulating ATF4-mediated stress response.

Submit: New GeneRIF Correction See all GeneRIFs (259)

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)

HIV-1 interactions

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Protein interactions

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

Go to the HIV-1, Human Interaction Database

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	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 factor activity	IDA Inferred from Direct Assay more info	PubMed
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
enables DNA-binding transcription factor activity, RNA polymerase II-specific	ISA Inferred from Sequence Alignment 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 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 protein binding	IPI Inferred from Physical Interaction more info	PubMed
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	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	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	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 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	ISS Inferred from Sequence or Structural Similarity more info
involved_in embryonic hemopoiesis	ISS Inferred from Sequence or Structural Similarity 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	NAS Non-traceable Author Statement more info	PubMed
involved_in intracellular calcium ion homeostasis	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	ISS Inferred from Sequence or Structural Similarity 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	ISS Inferred from Sequence or Structural Similarity more info	PubMed
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	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	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 biomineral tissue development	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	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of sodium-dependent phosphate transport	IEA Inferred from Electronic Annotation 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	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of transcription by RNA polymerase II	ISO Inferred from Sequence Orthology more info
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 associated smooth muscle cell apoptotic process	IEA Inferred from Electronic Annotation more info
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	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of osteoblast differentiation	IDA Inferred from Direct Assay more info	PubMed
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	ISO Inferred from Sequence Orthology 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	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 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 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 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	IPI Inferred from Physical Interaction more info	PubMed
part_of RNA polymerase II transcription regulator complex	ISO Inferred from Sequence Orthology more info
colocalizes_with centrosome	IDA Inferred from Direct Assay more info	PubMed
part_of chromatin	ISA Inferred from Sequence Alignment more info
located_in cytoplasm	IDA Inferred from Direct Assay more info	PubMed
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	ISS Inferred from Sequence or Structural Similarity more info
located_in nucleus	NAS Non-traceable Author Statement more info	PubMed
part_of protein-containing complex	IDA Inferred from Direct Assay more info	PubMed

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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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_2023_10

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