Details of Drug Off-Target (DOT)

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

• DOT Name: CREB-regulated transcription coactivator 3 (CRTC3)
• Synonyms: Transducer of regulated cAMP response element-binding protein 3; TORC-3; Transducer of CREB protein 3
• Gene Name: CRTC3
• Related Disease:
  Metabolic disorder
  Neoplasm
  Acute coronary syndrome
  Benign neoplasm of sweat gland
  Cholangiocarcinoma
  Colon cancer
  Colonic disorder
  Colorectal adenocarcinoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Inflammatory bowel disease
  Obesity
  Perianal crohn disease
  Crohn disease
• UniProt ID: CRTC3_HUMAN
• Pfam ID: PF12886 ; PF12885 ; PF12884
• Sequence:
  MAASPGSGSANPRKFSEKIALHTQRQAEETRAFEQLMTDLTLSRVQFQKLQQLRLTQYHG
  GSLPNVSQLRSSASEFQPSFHQADNVRGTRHHGLVERPSRNRFHPLHRRSGDKPGRQFDG
  SAFGANYSSQPLDESWPRQQPPWKDEKHPGFRLTSALNRTNSDSALHTSALSTKPQDPYG
  GGGQSAWPAPYMGFCDGENNGHGEVASFPGPLKEENLLNVPKPLPKQLWETKEIQSLSGR
  PRSCDVGGGNAFPHNGQNLGLSPFLGTLNTGGSLPDLTNLHYSTPLPASLDTTDHHFGSM
  SVGNSVNNIPAAMTHLGIRSSSGLQSSRSNPSIQATLNKTVLSSSLNNHPQTSVPNASAL
  HPSLRLFSLSNPSLSTTNLSGPSRRRQPPVSPLTLSPGPEAHQGFSRQLSSTSPLAPYPT
  SQMVSSDRSQLSFLPTEAQAQVSPPPPYPAPQELTQPLLQQPRAPEAPAQQPQAASSLPQ
  SDFQLLPAQGSSLTNFFPDVGFDQQSMRPGPAFPQQVPLVQQGSRELQDSFHLRPSPYSN
  CGSLPNTILPEDSSTSLFKDLNSALAGLPEVSLNVDTPFPLEEELQIEPLSLDGLNMLSD
  SSMGLLDPSVEETFRADRL
• Function: Transcriptional coactivator for CREB1 which activates transcription through both consensus and variant cAMP response element (CRE) sites. Acts as a coactivator, in the SIK/TORC signaling pathway, being active when dephosphorylated and acts independently of CREB1 'Ser-133' phosphorylation. Enhances the interaction of CREB1 with TAF4. Regulates the expression of specific CREB-activated genes such as the steroidogenic gene, StAR. Potent coactivator of PPARGC1A and inducer of mitochondrial biogenesis in muscle cells. Also coactivator for TAX activation of the human T-cell leukemia virus type 1 (HTLV-1) long terminal repeats (LTR).
• Tissue Specificity: Predominantly expressed in B and T lymphocytes. Highest levels in lung. Also expressed in brain, colon, heart, kidney, ovary, and prostate. Weak expression in liver, pancreas, muscle, small intestine, spleen and stomach.
• KEGG Pathway: Human T-cell leukemia virus 1 infection (hsa05166)
• Reactome Pathway:
  Circadian Clock (R-HSA-400253)
  Heme signaling (R-HSA-9707616)
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Metabolic disorder	DIS71G5H	Definitive	Genetic Variation	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Acute coronary syndrome	DIS7DYEW	Strong	Genetic Variation	[3]
Benign neoplasm of sweat gland	DISRJ557	Strong	Biomarker	[4]
Cholangiocarcinoma	DIS71F6X	Strong	Genetic Variation	[3]
Colon cancer	DISVC52G	Strong	Genetic Variation	[5]
Colonic disorder	DISXXS3L	Strong	Genetic Variation	[6]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[5]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[5]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[5]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[5]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[5]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[5]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[7]
Obesity	DIS47Y1K	Strong	Biomarker	[8]
Perianal crohn disease	DISOV578	Strong	Biomarker	[6]
Crohn disease	DIS2C5Q8	moderate	Genetic Variation	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of CREB-regulated transcription coactivator 3 (CRTC3).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of CREB-regulated transcription coactivator 3 (CRTC3).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of CREB-regulated transcription coactivator 3 (CRTC3).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of CREB-regulated transcription coactivator 3 (CRTC3).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of CREB-regulated transcription coactivator 3 (CRTC3).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of CREB-regulated transcription coactivator 3 (CRTC3).	[15]
Marinol	DM70IK5	Approved	Marinol increases the expression of CREB-regulated transcription coactivator 3 (CRTC3).	[16]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of CREB-regulated transcription coactivator 3 (CRTC3).	[18]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of CREB-regulated transcription coactivator 3 (CRTC3).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of CREB-regulated transcription coactivator 3 (CRTC3).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of CREB-regulated transcription coactivator 3 (CRTC3).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of CREB-regulated transcription coactivator 3 (CRTC3).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of CREB-regulated transcription coactivator 3 (CRTC3).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of CREB-regulated transcription coactivator 3 (CRTC3).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of CREB-regulated transcription coactivator 3 (CRTC3).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of CREB-regulated transcription coactivator 3 (CRTC3).	[17]

References

• [1] CRTC3 polymorphisms were associated with the plasma level of total cholesterol and the risks of overweight and hypertriglyceridemia in a Chinese Han population.Mol Biol Rep. 2014 Jan;41(1):125-30. doi: 10.1007/s11033-013-2844-4. Epub 2013 Nov 22.
• [2] Clinicopathological significance of the CRTC3-MAML2 fusion transcript in mucoepidermoid carcinoma.Mod Pathol. 2009 Dec;22(12):1575-81. doi: 10.1038/modpathol.2009.126. Epub 2009 Sep 11.
• [3] Cyclic adenosine monophosphate-regulated transcriptional co-activator 3 polymorphism in Chinese patients with acute coronary syndrome.Medicine (Baltimore). 2018 Jul;97(27):e11382. doi: 10.1097/MD.0000000000011382.
• [4] A novel fusion gene CRTC3-MAML2 in hidradenoma: histopathological significance.Hum Pathol. 2017 Dec;70:55-61. doi: 10.1016/j.humpath.2017.10.004. Epub 2017 Oct 24.
• [5] Association analyses identify 31 new risk loci for colorectal cancer susceptibility.Nat Commun. 2019 May 14;10(1):2154. doi: 10.1038/s41467-019-09775-w.
• [6] Perianal Crohn's Disease is Associated with Distal Colonic Disease, Stricturing Disease Behavior, IBD-Associated Serologies and Genetic Variation in the JAK-STAT Pathway.Inflamm Bowel Dis. 2016 Apr;22(4):862-9. doi: 10.1097/MIB.0000000000000705.
• [7] Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
• [8] Regulation role of CRTC3 in skeletal muscle and adipose tissue.J Cell Physiol. 2018 Feb;233(2):818-821. doi: 10.1002/jcp.25917. Epub 2017 May 19.
• [9] Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.Nat Genet. 2015 Sep;47(9):979-986. doi: 10.1038/ng.3359. Epub 2015 Jul 20.
• [10] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] A new function of copper zinc superoxide dismutase: as a regulatory DNA-binding protein in gene expression in response to intracellular hydrogen peroxide. Nucleic Acids Res. 2019 Jun 4;47(10):5074-5085. doi: 10.1093/nar/gkz256.
• [15] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [16] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [17] 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.
• [18] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [19] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [20] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [23] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [24] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.