Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDMU3GP)

• DOT Name: Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3)
• Synonyms: cAMP-responsive element-binding protein 3-like protein 3; Transcription factor CREB-H
• Gene Name: CREB3L3
• Related Disease:
  Adenoma
  Arteriosclerosis
  Atherosclerosis
  Fatty liver disease
  Hepatitis B virus infection
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Hyperglyceridemia
  Hyperlipoproteinemia
  Hypertriglyceridemia
  Hypertriglyceridemia 1
• UniProt ID: CR3L3_HUMAN
• Pfam ID: PF00170
• Sequence:
  MNTDLAAGKMASAACSMDPIDSFELLDLLFDRQDGILRHVELGEGWGHVKDQQVLPNPDS
  DDFLSSILGSGDSLPSSPLWSPEGSDSGISEDLPSDPQDTPPRSGPATSPAGCHPAQPGK
  GPCLSYHPGNSCSTTTPGPVIQVPEASVTIDLEMWSPGGRICAEKPADPVDLSPRCNLTV
  KDLLLSGSSGDLQQHHLGASYLLRPGAGHCQELVLTEDEKKLLAKEGITLPTQLPLTKYE
  ERVLKKIRRKIRNKQSAQESRKKKKEYIDGLETRMSACTAQNQELQRKVLHLEKQNLSLL
  EQLKKLQAIVVQSTSKSAQTGTCVAVLLLSFALIILPSISPFGPNKTESPGDFAPVRVFS
  RTLHNDAASRVAADAVPGSEAPGPRPEADTTREESPGSPGADWGFQDTANLTNSTEELDN
  ATLVLRNATEGLGQVALLDWVAPGPSTGSGRAGLEAAGDEL
• Function: Transcription factor that may act during endoplasmic reticulum stress by activating unfolded protein response target genes. Activated in response to cAMP stimulation. In vitro, binds to the cAMP response element (CRE) and box-B element. Activates transcription through box-B element. Activates transcription through CRE. May function synergistically with ATF6. In acute inflammatory response, may activate expression of acute phase response (APR) genes. May be involved in growth suppression. Regulates FGF21 transcription. Plays a crucial role in the regulation of triglyceride metabolism and is required for the maintenance of normal plasma triglyceride concentrations.
• Tissue Specificity: Exclusively expressed in liver. Underexpressed in hepatocellular carcinoma tissues.
• 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:
  Assembly of active LPL and LIPC lipase complexes (R-HSA-8963889)
  CREB3 factors activate genes (R-HSA-8874211)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Altered Expression	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[3]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[4]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Hyperglyceridemia	DIS1M07D	Strong	Autosomal dominant	[7]
Hyperlipoproteinemia	DISVBLBO	Strong	Biomarker	[8]
Hypertriglyceridemia	DIS7SN6U	Strong	Autosomal dominant	[9]
Hypertriglyceridemia 1	DIS1RZMO	Limited	Autosomal dominant	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3).	[16]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3).	[17]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3).	[18]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3).	[19]
Ampicillin	DMHWE7P	Approved	Ampicillin decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3).	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3).	[21]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3).	[22]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3).	[23]
2-arachidonoylglycerol	DMM0KOJ	Investigative	2-arachidonoylglycerol increases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3).	[24]

References

• [1] Expression of cAMP-responsive element binding protein and inducible cAMP early repressor in hyperfunctioning thyroid adenomas.Eur J Endocrinol. 2002 Jun;146(6):759-66. doi: 10.1530/eje.0.1460759.
• [2] CREBH Regulates Systemic Glucose and Lipid Metabolism.Int J Mol Sci. 2018 May 8;19(5):1396. doi: 10.3390/ijms19051396.
• [3] Transcriptional regulation of apolipoprotein A-IV by the transcription factor CREBH.J Lipid Res. 2014 May;55(5):850-9. doi: 10.1194/jlr.M045104. Epub 2014 Mar 5.
• [4] HBx induces the proliferation of hepatocellular carcinoma cells via AP1 over-expressed as a result of ER stress.Biochem J. 2015 Feb 15;466(1):115-21. doi: 10.1042/BJ20140819.
• [5] Critical role of CREBH-mediated induction of transforming growth factor 2 by hepatitis C virus infection in fibrogenic responses in hepatic stellate cells.Hepatology. 2017 Nov;66(5):1430-1443. doi: 10.1002/hep.29319. Epub 2017 Sep 29.
• [6] HELLS Regulates Chromatin Remodeling and Epigenetic Silencing of Multiple Tumor Suppressor Genes in Human Hepatocellular Carcinoma.Hepatology. 2019 May;69(5):2013-2030. doi: 10.1002/hep.30414. Epub 2019 Mar 27.
• [7] The transcription factor cyclic AMP-responsive element-binding protein H regulates triglyceride metabolism. Nat Med. 2011 Jun 12;17(7):812-5. doi: 10.1038/nm.2347.
• [8] CREBH mediates metabolic inflammation to hepatic VLDL overproduction and hyperlipoproteinemia.J Mol Med (Berl). 2017 Aug;95(8):839-849. doi: 10.1007/s00109-017-1534-4. Epub 2017 Apr 28.
• [9] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [10] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [11] 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.
• [12] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [13] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [16] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [19] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [20] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [23] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [24] Hepatic cannabinoid receptor type 1 mediates alcohol-induced regulation of bile acid enzyme genes expression via CREBH. PLoS One. 2013 Jul 22;8(7):e68845.