ATF4 (activating transcription factor 4)

Gene

• Entrez ID: 468
• Gene name: Activating transcription factor 4
• Gene symbol: ATF4
• Synonyms: 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 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]

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT007201	hsa-miR-214-3p	Luciferase reporter assay	23223004
MIRT042655	hsa-miR-196b-5p	CLASH	23622248
MIRT043684	hsa-miR-342-3p	CLASH	23622248
MIRT735484	hsa-miR-1283	Luciferase reporter assay, qRT-PCR, Western blot	27537404

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	ISS
GO:0000785	Component	Chromatin	ISA
GO:0000976	Function	Transcription regulatory region sequence-specific DNA binding	IDA	21113145
GO:0000976	Function	Transcription regulatory region sequence-specific DNA binding	IDA	12871976
GO:0000976	Function	Transcription regulatory region sequence-specific DNA binding	TAS	23392669
GO:0000977	Function	RNA polymerase II transcription regulatory region sequence-specific DNA binding	IBA	21873635
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	ISA
GO:0001085	Function	RNA polymerase II transcription factor binding	IPI	11478948
GO:0001228	Function	DNA-binding transcription activator activity, RNA polymerase II-specific	IBA	21873635
GO:0003677	Function	DNA binding	IDA	15788408, 15911876, 18940792
GO:0003677	Function	DNA binding	ISS
GO:0003700	Function	DNA-binding transcription factor activity	IDA	11960987, 15109498, 23123191, 32132707
GO:0003700	Function	DNA-binding transcription factor activity	TAS	12689582
GO:0005515	Function	Protein binding	IPI	9488481, 11238952, 12743605, 12812986, 12860379, 15677469, 15911876, 16169070, 16189514, 16343488, 16682973, 18330356, 18940792, 19164757, 19447967, 20102225, 20936779, 21408167, 21988832, 23123191, 25241761, 25416956, 25910212, 26700459, 26871637, 29892012, 31413325, 31515488, 3229
GO:0005634	Component	Nucleus	IBA	21873635
GO:0005634	Component	Nucleus	IDA	11478948, 16682973, 23123191, 23392669
GO:0005634	Component	Nucleus	ISS
GO:0005654	Component	Nucleoplasm	TAS
GO:0005737	Component	Cytoplasm	IDA	23392669
GO:0005737	Component	Cytoplasm	ISS
GO:0005813	Component	Centrosome	IDA	20873783
GO:0006094	Process	Gluconeogenesis	ISS
GO:0006355	Process	Regulation of transcription, DNA-templated	ISS
GO:0006357	Process	Regulation of transcription by RNA polymerase II	IBA	21873635
GO:0006366	Process	Transcription by RNA polymerase II	ISS
GO:0006874	Process	Cellular calcium ion homeostasis	IEA
GO:0007214	Process	Gamma-aminobutyric acid signaling pathway	IEA
GO:0008022	Function	Protein C-terminus 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	IMP	16445384, 24136195, 24939851
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	ISS
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	ISS
GO:0032991	Component	Protein-containing complex	IDA	20873783
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	ISS
GO:0034644	Process	Cellular response to UV	ISS
GO:0034976	Process	Response to endoplasmic reticulum stress	IDA	19061639
GO:0034976	Process	Response to endoplasmic reticulum stress	IMP	24939851
GO:0035162	Process	Embryonic hemopoiesis	ISS
GO:0036003	Process	Positive regulation of transcription from RNA polymerase II promoter in response to stress	IC	25681212
GO:0036091	Process	Positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress	IMP	21113145
GO:0036091	Process	Positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress	ISS	23392669
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	ISS
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	ISS
GO:0043565	Function	Sequence-specific DNA binding	IDA	22915762
GO:0045667	Process	Regulation of osteoblast differentiation	IDA	15109498
GO:0045893	Process	Positive regulation of transcription, DNA-templated	IDA	15775988, 18940792
GO:0045893	Process	Positive regulation of transcription, DNA-templated	IMP	11960987
GO:0045893	Process	Positive regulation of transcription, DNA-templated	ISS
GO:0045893	Process	Positive regulation of transcription, DNA-templated	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, 15109498, 15775988, 18940792, 23123191
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	IMP	15788408
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	ISS
GO:0046982	Function	Protein heterodimerization activity	ISS
GO:0048167	Process	Regulation of synaptic plasticity	ISS
GO:0061395	Process	Positive regulation of transcription from RNA polymerase II promoter in response to arsenic-containing substance	TAS	14685163
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	ISS
GO:0070982	Process	L-asparagine metabolic process	IDA	11960987
GO:0090650	Process	Cellular response to oxygen-glucose deprivation	IEA
GO:0120163	Process	Negative regulation of cold-induced thermogenesis	ISS	22980225
GO:0140467	Process	Integrated stress response signaling	IDA	32132707
GO:0140468	Process	HRI-mediated signaling	IDA	32132707
GO:1903204	Process	Negative regulation of oxidative stress-induced neuron death	IGI	23392669
GO:1903351	Process	Cellular response to dopamine	IMP	24136195
GO:1905461	Process	Positive regulation of vascular associated smooth muscle cell apoptotic process	IEA
GO:1990037	Component	Lewy body core	IDA	23392669
GO:1990440	Process	Positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress	IDA	12871976
GO:1990440	Process	Positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress	IMP	21113145
GO:1990589	Component	ATF4-CREB1 transcription factor complex	IBA	21873635
GO:1990589	Component	ATF4-CREB1 transcription factor complex	IDA	12871976
GO:1990590	Component	ATF1-ATF4 transcription factor complex	IBA	21873635
GO:1990590	Component	ATF1-ATF4 transcription factor complex	IDA	12871976
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: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 element-binding protein 67) (TaxREB67)
• 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 factor during integrated stress response (ISR) (PubMed:17684156, PubMed:16682973, PubMed:31444471, PubMed:32132707). Binds to asymmetric CRE's as a heterodimer and to palindromic CRE's as a homodimer (By similarity). Core effector of the ISR, which is required for adaptation to various stress such as endoplasmic reticulum (ER) stress, amino acid starvation, mitochondrial stress or oxidative stress (PubMed:32132707). During ISR, ATF4 translation is induced via an alternative ribosome translation re-initiation mechanism in response to EIF2S1/eIF-2-alpha phosphorylation, and stress-induced ATF4 acts as a master transcription factor of stress-responsive genes in order to promote cell recovery (PubMed:32132706, PubMed:32132707). Promotes the transcription of genes linked to amino acid sufficiency and resistance to oxidative stress to protect cells against metabolic consequences of ER oxidation (By similarity). Activates the transcription of NLRP1, possibly in concert with other factors in response to ER stress (PubMed:26086088). Activates the transcription of asparagine synthetase (ASNS) in response to amino acid deprivation or ER stress (PubMed:11960987). However, when associated with DDIT3/CHOP, the transcriptional activation of the ASNS gene is inhibited in response to amino acid deprivation (PubMed:18940792). Together with DDIT3/CHOP, mediates programmed cell death by promoting the expression of genes involved in cellular amino acid metabolic processes, mRNA translation and the terminal unfolded protein response (terminal UPR), a cellular response that elicits programmed cell death when ER stress is prolonged and unresolved (By similarity). Together with DDIT3/CHOP, activates the transcription of the IRS-regulator TRIB3 and promotes ER stress-induced neuronal cell death by regulating the expression of BBC3/PUMA in response to ER stress (PubMed:15775988). May cooperate with the UPR transcriptional regulator QRICH1 to regulate ER protein homeostasis which is critical for cell viability in response to ER stress (PubMed:33384352). In the absence of stress, ATF4 translation is at low levels and it is required for normal metabolic processes such as embryonic lens formation, fetal liver hematopoiesis, bone development and synaptic plasticity (By similarity). Acts as a regulator of osteoblast differentiation in response to phosphorylation by RPS6KA3/RSK2: phosphorylation in osteoblasts enhances transactivation activity and promotes expression of osteoblast-specific genes and post-transcriptionally regulates the synthesis of Type I collagen, the main constituent of the bone matrix (PubMed:15109498). Cooperates with FOXO1 in osteoblasts to regulate glucose homeostasis through suppression of beta-cell production and decrease in insulin production (By similarity). Activates transcription of SIRT4 (By similarity). Regulates the circadian expression of the core clock component PER2 and the serotonin transporter SLC6A4 (By similarity). Binds in a circadian time-dependent manner to the cAMP response elements (CRE) in the SLC6A4 and PER2 promoters and periodically activates the transcription of these genes (By similarity). Mainly acts as a transcriptional activator in cellular stress adaptation, but it can also act as a transcriptional repressor: acts as a regulator of synaptic plasticity by repressing transcription, thereby inhibiting induction and maintenance of long-term memory (By similarity). Regulates synaptic functions via interaction with DISC1 in neurons, which inhibits ATF4 transcription factor activity by disrupting ATF4 dimerization and DNA-binding (PubMed:31444471). ; (Microbial infection) Binds to a Tax-responsive enhancer element in the long terminal repeat of HTLV-I.
• 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