ATF4 (activating transcription factor 4)

Gene

• Entrez ID: 468
• Gene name: Activating transcription factor 4
• Gene symbol: ATF4
• Synonyms (NCBI Gene): CREB-2, CREB2, TAXREB67, TXREB
• Chromosome: 22
• Chromosome location: 22q13.1
• 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

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT007201	hsa-miR-214-3p	Luciferase reporter assay	23223004
MIRT007201	hsa-miR-214-3p	Luciferase reporter assay	23223004
MIRT043684	hsa-miR-342-3p	CLASH	23622248
MIRT042655	hsa-miR-196b-5p	CLASH	23622248
MIRT735196	hsa-miR-124-3p	Western blotting, Immunohistochemistry (IHC), in vitro cullelar assays, qRT-PCR, Immunocytochemistry (ICC)	33161580
MIRT804281	hsa-miR-3120-3p	CLIP-seq
MIRT804282	hsa-miR-548v	CLIP-seq
MIRT804281	hsa-miR-3120-3p	CLIP-seq
MIRT804282	hsa-miR-548v	CLIP-seq
MIRT804281	hsa-miR-3120-3p	CLIP-seq
MIRT804282	hsa-miR-548v	CLIP-seq

Transcription factors

Transcription factor	Regulation	Reference
HDAC4	Unknown	24308964
IRF7	Activation	21148039
TRIB3	Repression	15781252;17707795

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000122	Process	Negative regulation of transcription by RNA polymerase II	IEA
GO:0000122	Process	Negative regulation of transcription by RNA polymerase II	ISS
GO:0000785	Component	Chromatin	ISA
GO:0000976	Function	Transcription cis-regulatory region binding	IDA	12871976
GO:0000976	Function	Transcription cis-regulatory region binding	IDA	21113145
GO:0000976	Function	Transcription cis-regulatory region binding	TAS	23392669
GO:0000977	Function	RNA polymerase II transcription regulatory region sequence-specific DNA binding	IBA
GO:0000978	Function	RNA polymerase II cis-regulatory region sequence-specific DNA binding	IEA
GO:0000978	Function	RNA polymerase II cis-regulatory region sequence-specific DNA binding	ISS
GO:0000981	Function	DNA-binding transcription factor activity, RNA polymerase II-specific	IDA	11478948, 12871976
GO:0000981	Function	DNA-binding transcription factor activity, RNA polymerase II-specific	IEA
GO:0000981	Function	DNA-binding transcription factor activity, RNA polymerase II-specific	ISA
GO:0001228	Function	DNA-binding transcription activator activity, RNA polymerase II-specific	IBA
GO:0001228	Function	DNA-binding transcription activator activity, RNA polymerase II-specific	IEA
GO:0003677	Function	DNA binding	IDA	15788408, 15911876, 18940792
GO:0003677	Function	DNA binding	IEA
GO:0003677	Function	DNA binding	ISS
GO:0003700	Function	DNA-binding transcription factor activity	IDA	11960987, 15109498, 23123191, 31023583, 32132707
GO:0003700	Function	DNA-binding transcription factor activity	IEA
GO:0003700	Function	DNA-binding transcription factor activity	TAS	12689582
GO:0005515	Function	Protein binding	IPI	9488481, 11238952, 12743605, 12812986, 12860379, 15677469, 16169070, 16189514, 16343488, 16682973, 18330356, 18940792, 19164757, 19447967, 20102225, 20211142, 20936779, 21408167, 21988832, 23123191, 23661758, 25241761, 25416956, 25910212, 26700459, 26871637, 28514442, 29892012, 3141
GO:0005634	Component	Nucleus	IBA
GO:0005634	Component	Nucleus	IDA	11478948, 16682973, 23123191, 23392669
GO:0005634	Component	Nucleus	IEA
GO:0005634	Component	Nucleus	ISS
GO:0005634	Component	Nucleus	NAS	12871976, 20102225, 23661758, 28186491
GO:0005654	Component	Nucleoplasm	IDA
GO:0005654	Component	Nucleoplasm	TAS
GO:0005667	Component	Transcription regulator complex	IEA
GO:0005737	Component	Cytoplasm	IDA	23392669
GO:0005737	Component	Cytoplasm	IEA
GO:0005737	Component	Cytoplasm	ISS
GO:0005739	Component	Mitochondrion	IEA
GO:0005813	Component	Centrosome	IDA	20873783
GO:0005813	Component	Centrosome	IEA
GO:0005829	Component	Cytosol	TAS
GO:0005856	Component	Cytoskeleton	IEA
GO:0005886	Component	Plasma membrane	IEA
GO:0006094	Process	Gluconeogenesis	IEA
GO:0006094	Process	Gluconeogenesis	ISS
GO:0006355	Process	Regulation of DNA-templated transcription	IEA
GO:0006355	Process	Regulation of DNA-templated transcription	IEA
GO:0006355	Process	Regulation of DNA-templated transcription	ISS
GO:0006357	Process	Regulation of transcription by RNA polymerase II	IBA
GO:0006357	Process	Regulation of transcription by RNA polymerase II	IEA
GO:0006357	Process	Regulation of transcription by RNA polymerase II	ISO
GO:0006357	Process	Regulation of transcription by RNA polymerase II	NAS	20102225, 23661758, 28186491
GO:0006366	Process	Transcription by RNA polymerase II	IEA
GO:0006366	Process	Transcription by RNA polymerase II	ISS
GO:0006874	Process	Intracellular calcium ion homeostasis	IEA
GO:0007214	Process	Gamma-aminobutyric acid signaling pathway	IEA
GO:0007623	Process	Circadian rhythm	IEA
GO:0008140	Function	CAMP response element binding protein binding	IEA
GO:0008140	Function	CAMP response element binding protein binding	ISS
GO:0009636	Process	Response to toxic substance	IEA
GO:0010575	Process	Positive regulation of vascular endothelial growth factor production	IMP	22915762
GO:0010628	Process	Positive regulation of gene expression	IEA
GO:0010628	Process	Positive regulation of gene expression	IMP	16445384
GO:0016020	Component	Membrane	IEA
GO:0016607	Component	Nuclear speck	IEA
GO:0019901	Function	Protein kinase binding	IPI	20873783
GO:0030182	Process	Neuron differentiation	IEA
GO:0030282	Process	Bone mineralization	IEA
GO:0030282	Process	Bone mineralization	ISS
GO:0030968	Process	Endoplasmic reticulum unfolded protein response	IEA
GO:0030968	Process	Endoplasmic reticulum unfolded protein response	ISS
GO:0031667	Process	Response to nutrient levels	IDA	11960987
GO:0032057	Process	Negative regulation of translational initiation in response to stress	ISS
GO:0032590	Component	Dendrite membrane	IEA
GO:0032922	Process	Circadian regulation of gene expression	IEA
GO:0032922	Process	Circadian regulation of gene expression	ISS
GO:0032991	Component	Protein-containing complex	IDA	20873783
GO:0034198	Process	Cellular response to amino acid starvation	IEA
GO:0034198	Process	Cellular response to amino acid starvation	ISS
GO:0034399	Component	Nuclear periphery	IDA	23392669
GO:0034599	Process	Cellular response to oxidative stress	IEA
GO:0034599	Process	Cellular response to oxidative stress	IMP	21113145, 23392669
GO:0034599	Process	Cellular response to oxidative stress	ISS
GO:0034644	Process	Cellular response to UV	ISS
GO:0034976	Process	Response to endoplasmic reticulum stress	IDA	12871976, 19061639, 33384352
GO:0034976	Process	Response to endoplasmic reticulum stress	IEA
GO:0034976	Process	Response to endoplasmic reticulum stress	IMP	21113145, 24939851
GO:0035162	Process	Embryonic hemopoiesis	IEA
GO:0035162	Process	Embryonic hemopoiesis	ISS
GO:0036499	Process	PERK-mediated unfolded protein response	IDA	31023583
GO:0036499	Process	PERK-mediated unfolded protein response	IEA
GO:0036499	Process	PERK-mediated unfolded protein response	ISS
GO:0036499	Process	PERK-mediated unfolded protein response	TAS	22013210, 22934019
GO:0042149	Process	Cellular response to glucose starvation	IMP	22915762
GO:0042789	Process	MRNA transcription by RNA polymerase II	IEA
GO:0042789	Process	MRNA transcription by RNA polymerase II	ISS
GO:0042802	Function	Identical protein binding	IPI	16343488, 23661758
GO:0042981	Process	Regulation of apoptotic process	IEA
GO:0043005	Component	Neuron projection	IDA	23392669
GO:0043065	Process	Positive regulation of apoptotic process	TAS	23392669
GO:0043267	Process	Negative regulation of potassium ion transport	IEA
GO:0043522	Function	Leucine zipper domain binding	IDA	11478948
GO:0043525	Process	Positive regulation of neuron apoptotic process	IEA
GO:0043525	Process	Positive regulation of neuron apoptotic process	ISS
GO:0043565	Function	Sequence-specific DNA binding	IDA	22915762
GO:0045667	Process	Regulation of osteoblast differentiation	IDA	15109498
GO:0045667	Process	Regulation of osteoblast differentiation	IEA
GO:0045893	Process	Positive regulation of DNA-templated transcription	IDA	15775988, 18940792
GO:0045893	Process	Positive regulation of DNA-templated transcription	IEA
GO:0045893	Process	Positive regulation of DNA-templated transcription	IMP	11960987
GO:0045893	Process	Positive regulation of DNA-templated transcription	ISS
GO:0045893	Process	Positive regulation of DNA-templated transcription	NAS	9190894
GO:0045943	Process	Positive regulation of transcription by RNA polymerase I	IMP	22915762
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	IDA	11478948, 11960987, 12871976, 15109498, 15775988, 16343488, 18940792, 23123191
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	IEA
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	IEA
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	IMP	15788408, 21113145, 24939851
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	ISO
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	ISS	23392669
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	TAS	14685163
GO:0046982	Function	Protein heterodimerization activity	IEA
GO:0046982	Function	Protein heterodimerization activity	ISS
GO:0048167	Process	Regulation of synaptic plasticity	IEA
GO:0048167	Process	Regulation of synaptic plasticity	ISS
GO:0048511	Process	Rhythmic process	IEA
GO:0061629	Function	RNA polymerase II-specific DNA-binding transcription factor binding	IPI	11478948
GO:0070059	Process	Intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	IEA
GO:0070059	Process	Intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	ISS
GO:0070169	Process	Positive regulation of biomineral tissue development	IEA
GO:0070309	Process	Lens fiber cell morphogenesis	IEA
GO:0070309	Process	Lens fiber cell morphogenesis	ISS
GO:0070982	Process	L-asparagine metabolic process	IDA	11960987
GO:0071456	Process	Cellular response to hypoxia	IEA
GO:0090575	Component	RNA polymerase II transcription regulator complex	IEA
GO:0090575	Component	RNA polymerase II transcription regulator complex	IPI	20102225, 23661758
GO:0090575	Component	RNA polymerase II transcription regulator complex	ISO
GO:0097250	Process	Mitochondrial respirasome assembly	IDA	27545886, 31023583
GO:0120163	Process	Negative regulation of cold-induced thermogenesis	IEA
GO:0120163	Process	Negative regulation of cold-induced thermogenesis	ISS	22980225
GO:0140296	Function	General transcription initiation factor binding	IEA
GO:0140297	Function	DNA-binding transcription factor binding	IEA
GO:0140467	Process	Integrated stress response signaling	IDA	32132707
GO:0140467	Process	Integrated stress response signaling	IEA
GO:0140467	Process	Integrated stress response signaling	NAS	28566324
GO:0140468	Process	HRI-mediated signaling	IDA	32132706, 32132707
GO:0160144	Process	GDF15-GFRAL signaling pathway	IDA	31535977
GO:1903377	Process	Negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway	IEA
GO:1903377	Process	Negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway	IGI	23392669
GO:1905461	Process	Positive regulation of vascular associated smooth muscle cell apoptotic process	IEA
GO:1990037	Component	Lewy body core	IDA	23392669
GO:1990253	Process	Cellular response to leucine starvation	IDA	17267404
GO:1990253	Process	Cellular response to leucine starvation	IEA
GO:1990589	Component	ATF4-CREB1 transcription factor complex	IBA
GO:1990589	Component	ATF4-CREB1 transcription factor complex	IDA	12871976
GO:1990589	Component	ATF4-CREB1 transcription factor complex	IEA
GO:1990590	Component	ATF1-ATF4 transcription factor complex	IBA
GO:1990590	Component	ATF1-ATF4 transcription factor complex	IDA	12871976
GO:1990590	Component	ATF1-ATF4 transcription factor complex	IEA
GO:1990617	Component	CHOP-ATF4 complex	IDA	11478948
GO:1990617	Component	CHOP-ATF4 complex	IPI	18940792
GO:1990617	Component	CHOP-ATF4 complex	NAS	15775988
GO:1990737	Process	Response to manganese-induced endoplasmic reticulum stress	IEA
GO:1990837	Function	Sequence-specific double-stranded DNA binding	IDA	28473536
GO:1990841	Function	Promoter-specific chromatin binding	IDA	17267404
GO:1990841	Function	Promoter-specific chromatin binding	IEA
GO:2000120	Process	Positive regulation of sodium-dependent phosphate transport	IEA

Other IDs

• MIM: 604064
• HGNC: 786
• e!Ensembl: ENSG00000128272

Protein

• UniProt ID: P18848
• Protein name: Cyclic AMP-dependent transcription factor ATF-4 (cAMP-dependent transcription factor ATF-4) (Activating transcription factor 4) (Cyclic AMP-responsive element-binding protein 2) (CREB-2) (cAMP-responsive element-binding protein 2) (Tax-responsive enhancer
• Protein function: Transcription factor that binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3') and displays two biological functions, as regulator of metabolic and redox processes under normal cellular conditions, and as master transcription
• PDB: 1CI6
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00170	bZIP_1	276 → 339	bZIP transcription factor	Coiled-coil

• Sequence:

  MTEMSFLSSEVLVGDLMSPFDQSGLGAEESLGLLDDYLEVAKHFKPHGFSSDKAKAGSSE
  WLAVDGLVSPSNNSKEDAFSGTDWMLEKMDLKEFDLDALLGIDDLETMPDDLLTTLDDTC
  DLFAPLVQETNKQPPQTVNPIGHLPESLTKPDQVAPFTFLQPLPLSPGVLSSTPDHSFSL
  ELGSEVDITEGDRKPDYTAYVAMIPQCIKEEDTPSDNDSGICMSPESYLGSPQHSPSTRG
  SPNRSLPSPGVLCGSARPKPYDPPGEKMVAAKVKGEKLDKKLKKMEQNKTAATRYRQKKR
  AEQEALTGECKELEKKNEALKERADSLAKEIQYLKDLIEEVRKARGKKRVP

• Sequence length: 351

Pathways

KEGG:

MAPK signaling pathway
cGMP-PKG signaling pathway
Mitophagy - animal
Protein processing in endoplasmic reticulum
PI3K-Akt signaling pathway
Apoptosis
Longevity regulating pathway
Adrenergic signaling in cardiomyocytes
TNF signaling pathway
Long-term potentiation
Neurotrophin signaling pathway
Cholinergic synapse
Dopaminergic synapse
Insulin secretion
GnRH signaling pathway
Estrogen signaling pathway
Thyroid hormone synthesis
Glucagon signaling pathway
Aldosterone synthesis and secretion
Relaxin signaling pathway
Cortisol synthesis and secretion
Parathyroid hormone synthesis, secretion and action
Non-alcoholic fatty liver disease
Cushing syndrome
Growth hormone synthesis, secretion and action
Alzheimer disease
Parkinson disease
Amyotrophic lateral sclerosis
Prion disease
Pathways of neurodegeneration - multiple diseases
Cocaine addiction
Amphetamine addiction
Alcoholism
Hepatitis B
Human cytomegalovirus infection
Human T-cell leukemia virus 1 infection
Viral carcinogenesis
Chemical carcinogenesis - receptor activation
Prostate cancer
Lipid and atherosclerosis

Reactome:

ATF4 activates genes in response to endoplasmic reticulum stress
ATF6 (ATF6-alpha) activates chaperone genes
Response of EIF2AK4 (GCN2) to amino acid deficiency
Response of EIF2AK1 (HRI) to heme deficiency