Browse ATF4

Summary
SymbolATF4
Nameactivating transcription factor 4
Aliases TAXREB67; tax-responsive enhancer element B67; TXREB; activating transcription factor 4 (tax-responsive enha ......
Chromosomal Location22q13.1
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Basic function annotation.
> Subcellular Location, Domain and Function
> Gene Ontology
> KEGG and Reactome Pathway
> Subcellular Location, Domain and Function
 
Subcellular Location Cytoplasm Cell membrane Nucleus Cytoplasm, cytoskeleton, microtubule organizing center, centrosome Note=Colocalizes with GABBR1 in hippocampal neuron dendritic membranes (By similarity). Colocalizes with NEK6 at the centrosome (PubMed:20873783).
Domain PF00170 bZIP transcription factor
Function

Transcriptional activator. Binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), a sequence present in many viral and cellular promoters. Cooperates with FOXO1 in osteoblasts to regulate glucose homeostasis through suppression of beta-cell production and decrease in insulin production (By similarity). It binds to a Tax-responsive enhancer element in the long terminal repeat of HTLV-I. Regulates the induction of DDIT3/CHOP and asparagine synthetase (ASNS) in response to endoplasmic reticulum (ER) stress. In concert with DDIT3/CHOP, activates the transcription of TRIB3 and promotes ER stress-induced neuronal apoptosis by regulating the transcriptional induction of BBC3/PUMA. Activates transcription of SIRT4. Regulates the circadian expression of the core clock component PER2 and the serotonin transporter SLC6A4. 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. During ER stress response, activates the transcription of NLRP1, possibly in concert with other factors (PubMed:26086088).

> Gene Ontology
 
Biological Process GO:0001819 positive regulation of cytokine production
GO:0005996 monosaccharide metabolic process
GO:0006006 glucose metabolic process
GO:0006094 gluconeogenesis
GO:0006356 regulation of transcription from RNA polymerase I promoter
GO:0006360 transcription from RNA polymerase I promoter
GO:0006413 translational initiation
GO:0006417 regulation of translation
GO:0006446 regulation of translational initiation
GO:0006520 cellular amino acid metabolic process
GO:0006813 potassium ion transport
GO:0006979 response to oxidative stress
GO:0006984 ER-nucleus signaling pathway
GO:0006986 response to unfolded protein
GO:0007214 gamma-aminobutyric acid signaling pathway
GO:0007623 circadian rhythm
GO:0009267 cellular response to starvation
GO:0009299 mRNA transcription
GO:0009314 response to radiation
GO:0009411 response to UV
GO:0009416 response to light stimulus
GO:0009991 response to extracellular stimulus
GO:0010035 response to inorganic substance
GO:0010038 response to metal ion
GO:0010042 response to manganese ion
GO:0010573 vascular endothelial growth factor production
GO:0010574 regulation of vascular endothelial growth factor production
GO:0010575 positive regulation of vascular endothelial growth factor production
GO:0010608 posttranscriptional regulation of gene expression
GO:0010959 regulation of metal ion transport
GO:0015672 monovalent inorganic cation transport
GO:0016051 carbohydrate biosynthetic process
GO:0017148 negative regulation of translation
GO:0019318 hexose metabolic process
GO:0019319 hexose biosynthetic process
GO:0030968 endoplasmic reticulum unfolded protein response
GO:0031667 response to nutrient levels
GO:0031668 cellular response to extracellular stimulus
GO:0031669 cellular response to nutrient levels
GO:0032055 negative regulation of translation in response to stress
GO:0032057 negative regulation of translational initiation in response to stress
GO:0032922 circadian regulation of gene expression
GO:0034198 cellular response to amino acid starvation
GO:0034248 regulation of cellular amide metabolic process
GO:0034249 negative regulation of cellular amide metabolic process
GO:0034599 cellular response to oxidative stress
GO:0034620 cellular response to unfolded protein
GO:0034644 cellular response to UV
GO:0034976 response to endoplasmic reticulum stress
GO:0035966 response to topologically incorrect protein
GO:0035967 cellular response to topologically incorrect protein
GO:0036003 positive regulation of transcription from RNA polymerase II promoter in response to stress
GO:0036091 positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress
GO:0036473 cell death in response to oxidative stress
GO:0036475 neuron death in response to oxidative stress
GO:0036499 PERK-mediated unfolded protein response
GO:0042149 cellular response to glucose starvation
GO:0042594 response to starvation
GO:0042789 mRNA transcription from RNA polymerase II promoter
GO:0043266 regulation of potassium ion transport
GO:0043267 negative regulation of potassium ion transport
GO:0043271 negative regulation of ion transport
GO:0043523 regulation of neuron apoptotic process
GO:0043525 positive regulation of neuron apoptotic process
GO:0043555 regulation of translation in response to stress
GO:0043558 regulation of translational initiation in response to stress
GO:0043618 regulation of transcription from RNA polymerase II promoter in response to stress
GO:0043619 regulation of transcription from RNA polymerase II promoter in response to oxidative stress
GO:0043620 regulation of DNA-templated transcription in response to stress
GO:0044283 small molecule biosynthetic process
GO:0044723 single-organism carbohydrate metabolic process
GO:0045943 positive regulation of transcription from RNA polymerase I promoter
GO:0045947 negative regulation of translational initiation
GO:0046364 monosaccharide biosynthetic process
GO:0046685 response to arsenic-containing substance
GO:0048511 rhythmic process
GO:0051051 negative regulation of transport
GO:0051402 neuron apoptotic process
GO:0061394 regulation of transcription from RNA polymerase II promoter in response to arsenic-containing substance
GO:0061395 positive regulation of transcription from RNA polymerase II promoter in response to arsenic-containing substance
GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
GO:0070997 neuron death
GO:0071214 cellular response to abiotic stimulus
GO:0071241 cellular response to inorganic substance
GO:0071243 cellular response to arsenic-containing substance
GO:0071248 cellular response to metal ion
GO:0071287 cellular response to manganese ion
GO:0071478 cellular response to radiation
GO:0071482 cellular response to light stimulus
GO:0071496 cellular response to external stimulus
GO:0097193 intrinsic apoptotic signaling pathway
GO:1900407 regulation of cellular response to oxidative stress
GO:1900408 negative regulation of cellular response to oxidative stress
GO:1901214 regulation of neuron death
GO:1901215 negative regulation of neuron death
GO:1901216 positive regulation of neuron death
GO:1901522 positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus
GO:1902882 regulation of response to oxidative stress
GO:1902883 negative regulation of response to oxidative stress
GO:1903201 regulation of oxidative stress-induced cell death
GO:1903202 negative regulation of oxidative stress-induced cell death
GO:1903203 regulation of oxidative stress-induced neuron death
GO:1903204 negative regulation of oxidative stress-induced neuron death
GO:1990267 response to transition metal nanoparticle
GO:1990440 positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress
GO:1990737 response to manganese-induced endoplasmic reticulum stress
Molecular Function GO:0000978 RNA polymerase II core promoter proximal region sequence-specific DNA binding
GO:0000982 transcription factor activity, RNA polymerase II core promoter proximal region sequence-specific binding
GO:0000987 core promoter proximal region sequence-specific DNA binding
GO:0001046 core promoter sequence-specific DNA binding
GO:0001047 core promoter binding
GO:0001076 transcription factor activity, RNA polymerase II transcription factor binding
GO:0001077 transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding
GO:0001085 RNA polymerase II transcription factor binding
GO:0001159 core promoter proximal region DNA binding
GO:0001228 transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding
GO:0008022 protein C-terminus binding
GO:0008134 transcription factor binding
GO:0030275 LRR domain binding
GO:0043522 leucine zipper domain binding
GO:0046982 protein heterodimerization activity
Cellular Component GO:0005667 transcription factor complex
GO:0016234 inclusion body
GO:0031252 cell leading edge
GO:0031253 cell projection membrane
GO:0031256 leading edge membrane
GO:0032589 neuron projection membrane
GO:0032590 dendrite membrane
GO:0034399 nuclear periphery
GO:0044798 nuclear transcription factor complex
GO:0090575 RNA polymerase II transcription factor complex
GO:0097413 Lewy body
GO:1990037 Lewy body core
GO:1990589 ATF4-CREB1 transcription factor complex
GO:1990590 ATF1-ATF4 transcription factor complex
GO:1990617 CHOP-ATF4 complex
> KEGG and Reactome Pathway
 
KEGG hsa04010 MAPK signaling pathway
hsa04022 cGMP-PKG signaling pathway
hsa04141 Protein processing in endoplasmic reticulum
hsa04151 PI3K-Akt signaling pathway
hsa04210 Apoptosis
hsa04261 Adrenergic signaling in cardiomyocytes
hsa04668 TNF signaling pathway
hsa04720 Long-term potentiation
hsa04722 Neurotrophin signaling pathway
hsa04725 Cholinergic synapse
hsa04728 Dopaminergic synapse
hsa04911 Insulin secretion
hsa04912 GnRH signaling pathway
hsa04915 Estrogen signaling pathway
hsa04918 Thyroid hormone synthesis
hsa04922 Glucagon signaling pathway
Reactome R-HSA-380994: ATF4 activates genes
R-HSA-381183: ATF6 (ATF6-alpha) activates chaperone genes
R-HSA-381033: ATF6 (ATF6-alpha) activates chaperones
R-HSA-392499: Metabolism of proteins
R-HSA-381042: PERK regulates gene expression
R-HSA-381119: Unfolded Protein Response (UPR)
Summary
SymbolATF4
Nameactivating transcription factor 4
Aliases TAXREB67; tax-responsive enhancer element B67; TXREB; activating transcription factor 4 (tax-responsive enha ......
Chromosomal Location22q13.1
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Literatures that report relations between ATF4 and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.
> Text Mining
 
  Literatures describing the relation between ATF4 and anti-tumor immunity in human cancer.
PMID Cancer type Relation to immunity Evidence sentences
28096186MelanomaInhibit immunity; Resistant to immunotherapyATF4, a key transcription mediator of the integrated stress response, also activates AXL and suppresses senescence to impose the MITF-low/AXL-high drug-resistant phenotype observed in human tumors.
Summary
SymbolATF4
Nameactivating transcription factor 4
Aliases TAXREB67; tax-responsive enhancer element B67; TXREB; activating transcription factor 4 (tax-responsive enha ......
Chromosomal Location22q13.1
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.
> High-throughput Screening
  Statistical results of ATF4 in screening data sets for detecting immune reponses.
PMID Screening System Cancer Type Cell Line Data Set Statistical Results Relation to immunity
29301958CRISPR-Cas9 melanomaB16F10Pmel-1 T cell NA/NS NA/NS
29301958CRISPR-Cas9 melanomaB16F10OT-1 T cell logFC: -1.87; FDR: 0.02150 Resistant to T cell-mediated killing
28783722CRISPR-Cas9 melanomaMel6242CT-CRISPR NA/NS NA/NS
28723893CRISPR-Cas9 melanomaB16GVAX+Anti-PD1 STARS Score: 4.13; FDR: 0.014 Resistant to T cell-mediated killing
28723893CRISPR-Cas9 melanomaB16GVAX NA/NS NA/NS
25691366RNAiBreast cancerMCF7Luc-CTL assay NA/NS NA/NS
24476824shRNAmelanomaB16Primary screen NA/NS NA/NS
24476824shRNAmelanomaB16Secondary screen NA/NS NA/NS
Summary
SymbolATF4
Nameactivating transcription factor 4
Aliases TAXREB67; tax-responsive enhancer element B67; TXREB; activating transcription factor 4 (tax-responsive enha ......
Chromosomal Location22q13.1
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets.
> Expression difference between responders and non-responders
> Mutation difference between responders and non-responders
> Expression difference between responders and non-responders
 
Points in the above scatter plot represent the expression difference of ATF4 in various data sets.
No PMID Cancer type Group Drug # Res # NRes Log2 (Fold Change) P value Anno
126997480MelanomaallAnti-PD-1 (pembrolizumab and nivolumab)1412-0.1660.49
226997480MelanomaMAPKiAnti-PD-1 (pembrolizumab and nivolumab)65-0.5870.877
326997480Melanomanon-MAPKiAnti-PD-1 (pembrolizumab and nivolumab)870.1440.958
428552987Urothelial cancerallAnti-PD-L1 (atezolizumab) 9160.0730.823
528552987Urothelial cancersmokingAnti-PD-L1 (atezolizumab) 590.0610.982
628552987Urothelial cancernon-smokingAnti-PD-L1 (atezolizumab) 470.090.979
729033130MelanomaallAnti-PD-1 (nivolumab) 26230.0190.97
829033130MelanomaNIV3-PROGAnti-PD-1 (nivolumab) 1511-0.0810.972
929033130MelanomaNIV3-NAIVEAnti-PD-1 (nivolumab) 11120.1440.955
1029301960Clear cell renal cell carcinoma (ccRCC)allAnti-PD-1 (nivolumab) 48-0.120.961
1129301960Clear cell renal cell carcinoma (ccRCC)VEGFRiAnti-PD-1 (nivolumab) 2001
1229301960Clear cell renal cell carcinoma (ccRCC)non-VEGFRiAnti-PD-1 (nivolumab) 280.1990.957
1329443960Urothelial cancerallAnti-PD-L1 (atezolizumab) 68230-0.0640.345
> Mutation difference between responders and non-responders
 
Points in the above scatter plot represent the mutation difference of ATF4 in various data sets.
No PMID Cancer type Group Drug # Res # NRes % Mut/Res % Mut/NRes % Diff (R vs NR) Pval Anno
125765070Non-small cell lung cancer (NSCLC)allAnti-PD-1 (pembrolizumab) 14177.107.10.452
225765070Non-small cell lung cancer (NSCLC)smokingAnti-PD-1 (pembrolizumab) 103100101
325765070Non-small cell lung cancer (NSCLC)non-smokingAnti-PD-1 (pembrolizumab) 4140001
426359337MelanomaallAnti-CTLA-4 (ipilimumab) 27730001
526359337MelanomaBRAFiAnti-CTLA-4 (ipilimumab) 0140001
626359337Melanomanon-BRAFiAnti-CTLA-4 (ipilimumab) 27590001
726997480MelanomaallAnti-PD-1 (pembrolizumab and nivolumab)211705.9-5.90.447
826997480MelanomaMAPKiAnti-PD-1 (pembrolizumab and nivolumab)860001
926997480Melanomanon-MAPKiAnti-PD-1 (pembrolizumab and nivolumab)131109.1-9.10.458
1028552987Urothelial cancerallAnti-PD-L1 (atezolizumab) 9160001
1128552987Urothelial cancersmokingAnti-PD-L1 (atezolizumab) 590001
1228552987Urothelial cancernon-smokingAnti-PD-L1 (atezolizumab) 470001
1329033130MelanomaallAnti-PD-1 (nivolumab) 38270001
1429033130MelanomaNIV3-PROGAnti-PD-1 (nivolumab) 22130001
1529033130MelanomaNIV3-NAIVEAnti-PD-1 (nivolumab) 16140001
1629301960Clear cell renal cell carcinoma (ccRCC)allAnti-PD-1 (nivolumab) 11130001
1729301960Clear cell renal cell carcinoma (ccRCC)VEGFRiAnti-PD-1 (nivolumab) 610001
1829301960Clear cell renal cell carcinoma (ccRCC)non-VEGFRiAnti-PD-1 (nivolumab) 5120001
Summary
SymbolATF4
Nameactivating transcription factor 4
Aliases TAXREB67; tax-responsive enhancer element B67; TXREB; activating transcription factor 4 (tax-responsive enha ......
Chromosomal Location22q13.1
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of ATF4. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.
> Lymphocyte
 
Summary
SymbolATF4
Nameactivating transcription factor 4
Aliases TAXREB67; tax-responsive enhancer element B67; TXREB; activating transcription factor 4 (tax-responsive enha ......
Chromosomal Location22q13.1
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of ATF4. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by ATF4.
> Immunoinhibitor
> Immunostimulator
> MHC molecule
> Immunoinhibitor
 
> Immunostimulator
 
> MHC molecule
 
Summary
SymbolATF4
Nameactivating transcription factor 4
Aliases TAXREB67; tax-responsive enhancer element B67; TXREB; activating transcription factor 4 (tax-responsive enha ......
Chromosomal Location22q13.1
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of ATF4. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene.
> Chemokine
> Receptor
> Chemokine
 
> Receptor
 
Summary
SymbolATF4
Nameactivating transcription factor 4
Aliases TAXREB67; tax-responsive enhancer element B67; TXREB; activating transcription factor 4 (tax-responsive enha ......
Chromosomal Location22q13.1
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Distribution of ATF4 expression across immune and molecular subtypes.
> Immune subtype
> Molecular subtype
> Immune subtype
 
> Molecular subtype
 
Summary
SymbolATF4
Nameactivating transcription factor 4
Aliases TAXREB67; tax-responsive enhancer element B67; TXREB; activating transcription factor 4 (tax-responsive enha ......
Chromosomal Location22q13.1
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Associations between ATF4 and clinical features.
> Overall survival analysis
> Cancer stage
> Tumor grade
> Overall survival
 
> Stage
 
> Grade
 
Summary
SymbolATF4
Nameactivating transcription factor 4
Aliases TAXREB67; tax-responsive enhancer element B67; TXREB; activating transcription factor 4 (tax-responsive enha ......
Chromosomal Location22q13.1
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Drugs targeting ATF4 collected from DrugBank database.
> Drugs from DrugBank database
 

  Details on drugs targeting ATF4.
ID Name Drug Type Targets #Targets
DB00852PseudoephedrineSmall MoleculeADRA1A, ADRA2A, ADRB1, ADRB2, ATF1, ATF2, ATF3, ATF4, ATF5, ATF6, ......20