Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2JHIHM)

• DOT Name: Cyclic AMP-responsive element-binding protein 3-like protein 1 (CREB3L1)
• Synonyms: cAMP-responsive element-binding protein 3-like protein 1; Old astrocyte specifically-induced substance; OASIS
• Gene Name: CREB3L1
• Related Disease:
  Alzheimer disease
  Anxiety
  Anxiety disorder
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Constipation
  Depression
  Endometriosis
  Fibrosarcoma
  Glioma
  Kidney neoplasm
  Major depressive disorder
  Malignant glioma
  Mood disorder
  Neoplasm
  Osteogenesis imperfecta
  Osteogenesis imperfecta type 16
  Peripheral arterial disease
  Postpartum depression
  Sarcoma
  Systemic lupus erythematosus
  Triple negative breast cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Acute myelogenous leukaemia
  Soft tissue sarcoma
  Stroke
  Osteogenesis imperfecta type 3
  Advanced cancer
  Ankylosing spondylitis
  Squamous cell carcinoma
• UniProt ID: CR3L1_HUMAN
• Pfam ID: PF00170
• Sequence:
  MDAVLEPFPADRLFPGSSFLDLGDLNESDFLNNAHFPEHLDHFTENMEDFSNDLFSSFFD
  DPVLDEKSPLLDMELDSPTPGIQAEHSYSLSGDSAPQSPLVPIKMEDTTQDAEHGAWALG
  HKLCSIMVKQEQSPELPVDPLAAPSAMAAAAAMATTPLLGLSPLSRLPIPHQAPGEMTQL
  PVIKAEPLEVNQFLKVTPEDLVQMPPTPPSSHGSDSDGSQSPRSLPPSSPVRPMARSSTA
  ISTSPLLTAPHKLQGTSGPLLLTEEEKRTLIAEGYPIPTKLPLTKAEEKALKRVRRKIKN
  KISAQESRRKKKEYVECLEKKVETFTSENNELWKKVETLENANRTLLQQLQKLQTLVTNK
  ISRPYKMAATQTGTCLMVAALCFVLVLGSLVPCLPEFSSGSQTVKEDPLAADGVYTASQM
  PSRSLLFYDDGAGLWEDGRSTLLPMEPPDGWEINPGGPAEQRPRDHLQHDHLDSTHETTK
  YLSEAWPKDGGNGTSPDFSHSKEWFHDRDLGPNTTIKLS
• Function: [Cyclic AMP-responsive element-binding protein 3-like protein 1]: Precursor of the transcription factor form (Processed cyclic AMP-responsive element-binding protein 3-like protein 1), which is embedded in the endoplasmic reticulum membrane with N-terminal DNA-binding and transcription activation domains oriented toward the cytosolic face of the membrane. In response to ER stress or DNA damage, transported to the Golgi, where it is cleaved in a site-specific manner by resident proteases S1P/MBTPS1 and S2P/MBTPS2. The released N-terminal cytosolic domain is translocated to the nucleus where it activates transcription of specific target genes involved in the cell-cycle progression inhibition ; [Processed cyclic AMP-responsive element-binding protein 3-like protein 1]: Transcription factor involved in cell type specific DNA damage and unfolded protein response (UPR). Binds the DNA consensus sequence 5'-GTGXGCXGC-3'. Plays a critical role in bone formation through the transcription of COL1A1, and possibly COL1A2, and the secretion of bone matrix proteins. Directly binds to the UPR element (UPRE)-like sequence in an osteoblast-specific COL1A1 promoter region and induces its transcription. Does not regulate COL1A1 in other tissues, such as skin. Required to protect astrocytes from ER stress-induced cell death. In astrocytes, binds to the cAMP response element (CRE) of the BiP/HSPA5 promoter and participate in its transcriptional activation. In astrocytes and osteoblasts, upon DNA damage, inhibits cell-cycle progression after G2/M phase by binding to promoters and activating transcription of genes encoding cell-cycle inhibitors, such as p21/CDKN1A. Required for TGFB1 to activate genes involved in the assembly of collagen extracellular matrix ; (Microbial infection) May play a role in limiting virus spread by inhibiting proliferation of virus-infected cells. Upon infection with diverse DNA and RNA viruses, inhibits cell-cycle progression by binding to promoters and activating transcription of genes encoding cell-cycle inhibitors, such as p21/CDKN1A.
• Tissue Specificity: Expressed in several tissues, with highest levels in pancreas and prostate. Expressed at relatively lower levels in brain.
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  PI3K-Akt sig.ling pathway (hsa04151)
  AMPK sig.ling pathway (hsa04152)
  Longevity regulating pathway (hsa04211)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  TNF sig.ling pathway (hsa04668)
  Thermogenesis (hsa04714)
  Cholinergic sy.pse (hsa04725)
  Dopaminergic sy.pse (hsa04728)
  Insulin secretion (hsa04911)
  Estrogen sig.ling pathway (hsa04915)
  Melanogenesis (hsa04916)
  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)
  Insulin resistance (hsa04931)
  Cushing syndrome (hsa04934)
  Growth hormone synthesis, secretion and action (hsa04935)
  Vasopressin-regulated water reabsorption (hsa04962)
  Huntington disease (hsa05016)
  Prion disease (hsa05020)
  Cocaine addiction (hsa05030)
  Amphetamine addiction (hsa05031)
  Alcoholism (hsa05034)
  Hepatitis B (hsa05161)
  Human cytomegalovirus infection (hsa05163)
  Human papillomavirus infection (hsa05165)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Viral carcinogenesis (hsa05203)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Prostate cancer (hsa05215)
• Reactome Pathway: CREB3 factors activate genes (R-HSA-8874211)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Anxiety	DISIJDBA	Strong	Biomarker	[2]
Anxiety disorder	DISBI2BT	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Constipation	DISRQXWI	Strong	Biomarker	[5]
Depression	DIS3XJ69	Strong	Biomarker	[2]
Endometriosis	DISX1AG8	Strong	Biomarker	[6]
Fibrosarcoma	DISWX7MU	Strong	Genetic Variation	[7]
Glioma	DIS5RPEH	Strong	Genetic Variation	[8]
Kidney neoplasm	DISBNZTN	Strong	Genetic Variation	[9]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[10]
Malignant glioma	DISFXKOV	Strong	Genetic Variation	[8]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[10]
Neoplasm	DISZKGEW	Strong	Altered Expression	[11]
Osteogenesis imperfecta	DIS7XQSD	Strong	Genetic Variation	[12]
Osteogenesis imperfecta type 16	DISVIZTJ	Strong	Autosomal recessive	[13]
Peripheral arterial disease	DIS78WFB	Strong	Genetic Variation	[14]
Postpartum depression	DIS08UKE	Strong	Biomarker	[2]
Sarcoma	DISZDG3U	Strong	Genetic Variation	[15]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[16]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[11]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[3]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[17]
Soft tissue sarcoma	DISSN8XB	moderate	Genetic Variation	[15]
Stroke	DISX6UHX	moderate	Biomarker	[18]
Osteogenesis imperfecta type 3	DISFJVSJ	Supportive	Autosomal dominant	[19]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[11]
Ankylosing spondylitis	DISRC6IR	Limited	Biomarker	[20]
Squamous cell carcinoma	DISQVIFL	Limited	Genetic Variation	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Cyclic AMP-responsive element-binding protein 3-like protein 1 (CREB3L1).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cyclic AMP-responsive element-binding protein 3-like protein 1 (CREB3L1).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 1 (CREB3L1).	[23]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 1 (CREB3L1).	[24]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 1 (CREB3L1).	[25]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 1 (CREB3L1).	[26]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 1 (CREB3L1).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 1 (CREB3L1).	[29]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the activity of Cyclic AMP-responsive element-binding protein 3-like protein 1 (CREB3L1).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 1 (CREB3L1).	[31]

References

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• [12] A homozygous pathogenic missense variant broadens the phenotypic and mutational spectrum of CREB3L1-related osteogenesis imperfecta.Hum Mol Genet. 2019 Jun 1;28(11):1801-1809. doi: 10.1093/hmg/ddz017.
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• [17] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [18] Validation of Bleeding Classifications in Coronary Artery Bypass Grafting.Am J Cardiol. 2017 Mar 1;119(5):727-733. doi: 10.1016/j.amjcard.2016.11.027. Epub 2016 Dec 3.
• [19] Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans. Orphanet J Rare Dis. 2013 Sep 30;8:154. doi: 10.1186/1750-1172-8-154.
• [20] Evolution of radiographic damage in ankylosing spondylitis: a 12 year prospective follow-up of the OASIS study.Ann Rheum Dis. 2015 Jan;74(1):52-9. doi: 10.1136/annrheumdis-2013-204055. Epub 2013 Aug 16.
• [21] Recurrent fusion transcripts in squamous cell carcinomas of the vulva.Oncotarget. 2017 Mar 7;8(10):16843-16850. doi: 10.18632/oncotarget.15167.
• [22] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [23] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [24] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
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• [27] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
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• [30] Transcriptional regulation of VEGFA by the endoplasmic reticulum stress transducer OASIS in ARPE-19 cells. PLoS One. 2013;8(1):e55155. doi: 10.1371/journal.pone.0055155. Epub 2013 Jan 30.
• [31] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.