Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT2ZGSR)

• DOT Name: Cyclic AMP-dependent transcription factor ATF-6 beta (ATF6B)
• Synonyms: cAMP-dependent transcription factor ATF-6 beta; Activating transcription factor 6 beta; ATF6-beta; Protein G13; cAMP response element-binding protein-related protein; Creb-rp; cAMP-responsive element-binding protein-like 1
• Gene Name: ATF6B
• Related Disease:
  B-cell neoplasm
  Blindness
  Rheumatoid arthritis
  Sarcoidosis
  Systemic lupus erythematosus
• UniProt ID: ATF6B_HUMAN
• Pfam ID: PF00170
• Sequence:
  MAELMLLSEIADPTRFFTDNLLSPEDWGLQNSTLYSGLDEVAEEQTQLFRCPEQDVPFDG
  SSLDVGMDVSPSEPPWELLPIFPDLQVKSEPSSPCSSSSLSSESSRLSTEPSSEALGVGE
  VLHVKTESLAPPLCLLGDDPTSSFETVQINVIPTSDDSSDVQTKIEPVSPCSSVNSEASL
  LSADSSSQAFIGEEVLEVKTESLSPSGCLLWDVPAPSLGAVQISMGPSLDGSSGKALPTR
  KPPLQPKPVVLTTVPMPSRAVPPSTTVLLQSLVQPPPVSPVVLIQGAIRVQPEGPAPSLP
  RPERKSIVPAPMPGNSCPPEVDAKLLKRQQRMIKNRESACQSRRKKKEYLQGLEARLQAV
  LADNQQLRRENAALRRRLEALLAENSELKLGSGNRKVVCIMVFLLFIAFNFGPVSISEPP
  SAPISPRMNKGEPQPRRHLLGFSEQEPVQGVEPLQGSSQGPKEPQPSPTDQPSFSNLTAF
  PGGAKELLLRDLDQLFLSSDCRHFNRTESLRLADELSGWVQRHQRGRRKIPQRAQERQKS
  QPRKKSPPVKAVPIQPPGPPERDSVGQLQLYRHPDRSQPAFLDAIDRREDTFYVVSFRRD
  HLLLPAISHNKTSRPKMSLVMPAMAPNETLSGRGAPGDYEEMMQIECEVMDTRVIHIKTS
  TVPPSLRKQPSPTPGNATGGPLPVSAASQAHQASHQPLYLNHP
• Function: [Cyclic AMP-dependent transcription factor ATF-6 beta]: Precursor of the transcription factor form (Processed cyclic AMP-dependent transcription factor ATF-6 beta), which is embedded in the endoplasmic reticulum membrane. Endoplasmic reticulum stress promotes processing of this form, releasing the transcription factor form that translocates into the nucleus, where it activates transcription of genes involved in the unfolded protein response (UPR) ; [Processed cyclic AMP-dependent transcription factor ATF-6 beta]: Transcription factor that acts in the unfolded protein response (UPR) pathway by activating UPR target genes induced during ER stress. Binds DNA on the 5'-CCAC[GA]-3' half of the ER stress response element (ERSE) (5'-CCAATN(9)CCAC[GA]-3') when NF-Y is bound to ERSE.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  Protein processing in endoplasmic reticulum (hsa04141)
  PI3K-Akt sig.ling pathway (hsa04151)
  Longevity regulating pathway (hsa04211)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  TNF sig.ling pathway (hsa04668)
  Dopaminergic sy.pse (hsa04728)
  Insulin secretion (hsa04911)
  Estrogen sig.ling pathway (hsa04915)
  Thyroid hormone synthesis (hsa04918)
  Aldosterone synthesis and secretion (hsa04925)
  Relaxin sig.ling pathway (hsa04926)
  Cortisol synthesis and secretion (hsa04927)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Cushing syndrome (hsa04934)
  Growth hormone synthesis, secretion and action (hsa04935)
  Prion disease (hsa05020)
  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)
• Reactome Pathway: ATF6B (ATF6-beta) activates chaperones (R-HSA-8874177)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Strong	Altered Expression	[1]
Blindness	DISTIM10	Strong	Genetic Variation	[2]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[3]
Sarcoidosis	DISE5B8Z	Strong	Genetic Variation	[4]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[5]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Cyclic AMP-dependent transcription factor ATF-6 beta (ATF6B).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Cyclic AMP-dependent transcription factor ATF-6 beta (ATF6B).	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Cyclic AMP-dependent transcription factor ATF-6 beta (ATF6B).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Cyclic AMP-dependent transcription factor ATF-6 beta (ATF6B).	[16]

11 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cyclic AMP-dependent transcription factor ATF-6 beta (ATF6B).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Cyclic AMP-dependent transcription factor ATF-6 beta (ATF6B).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Cyclic AMP-dependent transcription factor ATF-6 beta (ATF6B).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Cyclic AMP-dependent transcription factor ATF-6 beta (ATF6B).	[10]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Cyclic AMP-dependent transcription factor ATF-6 beta (ATF6B).	[11]
Acocantherin	DM7JT24	Approved	Acocantherin increases the expression of Cyclic AMP-dependent transcription factor ATF-6 beta (ATF6B).	[12]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Cyclic AMP-dependent transcription factor ATF-6 beta (ATF6B).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Cyclic AMP-dependent transcription factor ATF-6 beta (ATF6B).	[17]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Cyclic AMP-dependent transcription factor ATF-6 beta (ATF6B).	[18]
3,7,3',4'-TETRAHYDROXYFLAVONE	DMES906	Investigative	3,7,3',4'-TETRAHYDROXYFLAVONE increases the expression of Cyclic AMP-dependent transcription factor ATF-6 beta (ATF6B).	[19]
L-Serine	DM6WPIS	Investigative	L-Serine increases the expression of Cyclic AMP-dependent transcription factor ATF-6 beta (ATF6B).	[20]

References

• [1] Quercetin induced apoptosis of human oral cancer SAS cells through mitochondria and endoplasmic reticulum mediated signaling pathways.Oncol Lett. 2018 Jun;15(6):9663-9672. doi: 10.3892/ol.2018.8584. Epub 2018 Apr 26.
• [2] The unfolded protein response regulator ATF6 promotes mesodermal differentiation.Sci Signal. 2018 Feb 13;11(517):eaan5785. doi: 10.1126/scisignal.aan5785.
• [3] A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis.Ann Rheum Dis. 2011 Feb;70(2):259-65. doi: 10.1136/ard.2009.126821. Epub 2010 Dec 14.
• [4] High-Density Genetic Mapping Identifies New Susceptibility Variants in Sarcoidosis Phenotypes and Shows Genomic-driven Phenotypic Differences.Am J Respir Crit Care Med. 2016 May 1;193(9):1008-22. doi: 10.1164/rccm.201507-1372OC.
• [5] High-density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions.PLoS Genet. 2009 Oct;5(10):e1000696. doi: 10.1371/journal.pgen.1000696. Epub 2009 Oct 23.
• [6] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Quercetin induced cell apoptosis and altered gene expression in AGS human gastric cancer cells. Environ Toxicol. 2018 Nov;33(11):1168-1181. doi: 10.1002/tox.22623. Epub 2018 Aug 27.
• [9] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
• [12] Ouabain induces apoptotic cell death in human prostate DU 145 cancer cells through DNA damage and TRAIL pathways. Environ Toxicol. 2019 Dec;34(12):1329-1339. doi: 10.1002/tox.22834. Epub 2019 Aug 21.
• [13] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [14] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [15] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [16] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [19] Fisetin-induced apoptosis of human oral cancer SCC-4 cells through reactive oxygen species production, endoplasmic reticulum stress, caspase-, and mitochondria-dependent signaling pathways. Environ Toxicol. 2017 Jun;32(6):1725-1741. doi: 10.1002/tox.22396. Epub 2017 Feb 9.
• [20] Mechanisms of L-Serine Neuroprotection in vitro Include ER Proteostasis Regulation. Neurotox Res. 2018 Jan;33(1):123-132. doi: 10.1007/s12640-017-9829-3. Epub 2017 Nov 2.