Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRFV19J)

DOT Name Cyclic AMP-dependent transcription factor ATF-4 (ATF4)
Synonyms
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
Gene Name ATF4
UniProt ID
ATF4_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
1CI6
Pfam ID
PF00170
Sequence
MTEMSFLSSEVLVGDLMSPFDQSGLGAEESLGLLDDYLEVAKHFKPHGFSSDKAKAGSSE
WLAVDGLVSPSNNSKEDAFSGTDWMLEKMDLKEFDLDALLGIDDLETMPDDLLTTLDDTC
DLFAPLVQETNKQPPQTVNPIGHLPESLTKPDQVAPFTFLQPLPLSPGVLSSTPDHSFSL
ELGSEVDITEGDRKPDYTAYVAMIPQCIKEEDTPSDNDSGICMSPESYLGSPQHSPSTRG
SPNRSLPSPGVLCGSARPKPYDPPGEKMVAAKVKGEKLDKKLKKMEQNKTAATRYRQKKR
AEQEALTGECKELEKKNEALKERADSLAKEIQYLKDLIEEVRKARGKKRVP
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). Binds to asymmetric CRE's as a heterodimer and to palindromic CRE's as a homodimer. 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. 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. Promotes the transcription of genes linked to amino acid sufficiency and resistance to oxidative stress to protect cells against metabolic consequences of ER oxidation. Activates the transcription of NLRP1, possibly in concert with other factors in response to ER stress. Activates the transcription of asparagine synthetase (ASNS) in response to amino acid deprivation or ER stress. However, when associated with DDIT3/CHOP, the transcriptional activation of the ASNS gene is inhibited in response to amino acid deprivation. 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. 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. May cooperate with the UPR transcriptional regulator QRICH1 to regulate ER protein homeostasis which is critical for cell viability in response to ER stress. 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. 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. Cooperates with FOXO1 in osteoblasts to regulate glucose homeostasis through suppression of beta-cell production and decrease in insulin production. 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. 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. Regulates synaptic functions via interaction with DISC1 in neurons, which inhibits ATF4 transcription factor activity by disrupting ATF4 dimerization and DNA-binding ; (Microbial infection) Binds to a Tax-responsive enhancer element in the long terminal repeat of HTLV-I.
KEGG Pathway
MAPK sig.ling pathway (hsa04010 )
cGMP-PKG sig.ling pathway (hsa04022 )
Mitophagy - animal (hsa04137 )
Protein processing in endoplasmic reticulum (hsa04141 )
PI3K-Akt sig.ling pathway (hsa04151 )
Apoptosis (hsa04210 )
Longevity regulating pathway (hsa04211 )
Adrenergic sig.ling in cardiomyocytes (hsa04261 )
TNF sig.ling pathway (hsa04668 )
Long-term potentiation (hsa04720 )
Neurotrophin sig.ling pathway (hsa04722 )
Cholinergic sy.pse (hsa04725 )
Dopaminergic sy.pse (hsa04728 )
Insulin secretion (hsa04911 )
GnRH sig.ling pathway (hsa04912 )
Estrogen sig.ling pathway (hsa04915 )
Thyroid hormone synthesis (hsa04918 )
Glucagon sig.ling pathway (hsa04922 )
Aldosterone synthesis and secretion (hsa04925 )
Relaxin sig.ling pathway (hsa04926 )
Cortisol synthesis and secretion (hsa04927 )
Parathyroid hormone synthesis, secretion and action (hsa04928 )
Non-alcoholic fatty liver disease (hsa04932 )
Cushing syndrome (hsa04934 )
Growth hormone synthesis, secretion and action (hsa04935 )
Alzheimer disease (hsa05010 )
Parkinson disease (hsa05012 )
Amyotrophic lateral sclerosis (hsa05014 )
Prion disease (hsa05020 )
Pathways of neurodegeneration - multiple diseases (hsa05022 )
Cocaine addiction (hsa05030 )
Amphetamine addiction (hsa05031 )
Alcoholism (hsa05034 )
Hepatitis B (hsa05161 )
Human cytomegalovirus infection (hsa05163 )
Human T-cell leukemia virus 1 infection (hsa05166 )
Viral carcinogenesis (hsa05203 )
Chemical carcinogenesis - receptor activation (hsa05207 )
Prostate cancer (hsa05215 )
Lipid and atherosclerosis (hsa05417 )
Reactome Pathway
PERK regulates gene expression (R-HSA-381042 )
ATF6 (ATF6-alpha) activates chaperone genes (R-HSA-381183 )
Response of EIF2AK4 (GCN2) to amino acid deficiency (R-HSA-9633012 )
Response of EIF2AK1 (HRI) to heme deficiency (R-HSA-9648895 )
NFE2L2 regulating anti-oxidant/detoxification enzymes (R-HSA-9818027 )
NFE2L2 regulating ER-stress associated genes (R-HSA-9818035 )
ATF4 activates genes in response to endoplasmic reticulum stress (R-HSA-380994 )

Molecular Interaction Atlas (MIA) of This DOT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
This DOT Affected the Drug Response of 1 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
D-glucose DMMG2TO Investigative Cyclic AMP-dependent transcription factor ATF-4 (ATF4) increases the response to substance of D-glucose. [76]
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86 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [1]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [2]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [3]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [4]
Cisplatin DMRHGI9 Approved Cisplatin affects the activity of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [5]
Ivermectin DMDBX5F Approved Ivermectin increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [6]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [7]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide decreases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [8]
Triclosan DMZUR4N Approved Triclosan decreases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [9]
Carbamazepine DMZOLBI Approved Carbamazepine increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [10]
Marinol DM70IK5 Approved Marinol decreases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [11]
Zoledronate DMIXC7G Approved Zoledronate decreases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [12]
Selenium DM25CGV Approved Selenium increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [13]
Phenobarbital DMXZOCG Approved Phenobarbital affects the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [14]
Progesterone DMUY35B Approved Progesterone increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [15]
Fluorouracil DMUM7HZ Approved Fluorouracil increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [16]
Niclosamide DMJAGXQ Approved Niclosamide increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [17]
Bortezomib DMNO38U Approved Bortezomib increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [18]
Hydroquinone DM6AVR4 Approved Hydroquinone increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [19]
Ethanol DMDRQZU Approved Ethanol increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [20]
Aspirin DM672AH Approved Aspirin decreases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [21]
Paclitaxel DMLB81S Approved Paclitaxel increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [22]
Diclofenac DMPIHLS Approved Diclofenac increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [10]
Piroxicam DMTK234 Approved Piroxicam decreases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [23]
Mitomycin DMH0ZJE Approved Mitomycin increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [24]
Cidofovir DMA13GD Approved Cidofovir affects the activity of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [5]
Fenofibrate DMFKXDY Approved Fenofibrate affects the activity of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [5]
Rifampicin DM5DSFZ Approved Rifampicin increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [25]
Ifosfamide DMCT3I8 Approved Ifosfamide affects the activity of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [5]
Clodronate DM9Y6X7 Approved Clodronate affects the activity of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [5]
Sulindac DM2QHZU Approved Sulindac increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [26]
Capsaicin DMGMF6V Approved Capsaicin increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [27]
Ibuprofen DM8VCBE Approved Ibuprofen affects the activity of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [5]
Methamphetamine DMPM4SK Approved Methamphetamine increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [28]
Sorafenib DMS8IFC Approved Sorafenib increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [29]
Ursodeoxycholic acid DMCUT21 Approved Ursodeoxycholic acid decreases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [30]
Sodium phenylbutyrate DMXLBCQ Approved Sodium phenylbutyrate decreases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [31]
Sertraline DM0FB1J Approved Sertraline increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [32]
Nefazodone DM4ZS8M Approved Nefazodone increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [33]
Glucosamine DM4ZLFD Approved Glucosamine increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [34]
Orlistat DMRJSP8 Approved Orlistat increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [35]
Atazanavir DMSYRBX Approved Atazanavir increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [33]
Cantharidin DMBP5N3 Approved Cantharidin increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [36]
Busulfan DMXYJ9C Approved Busulfan increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [37]
Nelfinavir mesylate DMFX6G8 Approved Nelfinavir mesylate increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [38]
Pitavastatin DMJH792 Approved Pitavastatin increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [39]
Pyrazinamide DM4IF32 Approved Pyrazinamide increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [40]
Bepridil DM0RKS4 Approved Bepridil increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [41]
Nitazoxanide DMOWLVG Approved Nitazoxanide increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [42]
Oxycodone DMXLKHV Approved Oxycodone increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [43]
Urethane DM7NSI0 Phase 4 Urethane increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [44]
Dihydrotestosterone DM3S8XC Phase 4 Dihydrotestosterone increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [45]
Cibenzoline DMBG0N4 Phase 4 Cibenzoline increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [41]
Curcumin DMQPH29 Phase 3 Curcumin decreases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [46]
Fenretinide DMRD5SP Phase 3 Fenretinide increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [47]
Camptothecin DM6CHNJ Phase 3 Camptothecin increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [48]
Psoralen DMIZJ8M Phase 3 Psoralen increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [49]
Amiodarone DMUTEX3 Phase 2/3 Trial Amiodarone decreases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [37]
Thymoquinone DMVDTR2 Phase 2/3 Thymoquinone increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [50]
ME-344 DM6JN19 Phase 1/2 ME-344 increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [51]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 decreases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [53]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [54]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [56]
Hydroxyqunoline analog 4 DMGQMCZ Patented Hydroxyqunoline analog 4 increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [57]
THAPSIGARGIN DMDMQIE Preclinical THAPSIGARGIN increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [3]
MG-132 DMKA2YS Preclinical MG-132 increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [58]
HELENALIN DMMCI4H Terminated HELENALIN increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [59]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [60]
Milchsaure DM462BT Investigative Milchsaure increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [61]
chloropicrin DMSGBQA Investigative chloropicrin affects the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [62]
Deguelin DMXT7WG Investigative Deguelin increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [63]
3R14S-OCHRATOXIN A DM2KEW6 Investigative 3R14S-OCHRATOXIN A decreases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [64]
Paraquat DMR8O3X Investigative Paraquat increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [65]
Glyphosate DM0AFY7 Investigative Glyphosate increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [66]
Lithium chloride DMHYLQ2 Investigative Lithium chloride increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [67]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE DMNQL17 Investigative 2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [68]
CATECHIN DMY38SB Investigative CATECHIN increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [69]
USNIC ACID DMGOURX Investigative USNIC ACID increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [70]
Hydroxydimethylarsine Oxide DMPS2B1 Investigative Hydroxydimethylarsine Oxide increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [71]
NORCANTHARIDIN DM9B6Y1 Investigative NORCANTHARIDIN increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [22]
P-Coumaric Acid DMGJSVD Investigative P-Coumaric Acid increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [16]
1,4-Dithiothreitol DMIFOXE Investigative 1,4-Dithiothreitol increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [72]
L-Serine DM6WPIS Investigative L-Serine increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [73]
All-trans-retinal DM6CEVB Investigative All-trans-retinal increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [74]
2-arachidonoylglycerol DMM0KOJ Investigative 2-arachidonoylglycerol increases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [75]
Tauroursodeoxycholic acid DMFKRQE Investigative Tauroursodeoxycholic acid decreases the expression of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [30]
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⏷ Show the Full List of 86 Drug(s)
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [52]
TAK-243 DM4GKV2 Phase 1 TAK-243 increases the sumoylation of Cyclic AMP-dependent transcription factor ATF-4 (ATF4). [55]
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