Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4R2TYK)

• DOT Name: Smoothelin (SMTN)
• Gene Name: SMTN
• Related Disease:
  Cerebral infarction
  Bladder cancer
  Esophageal adenocarcinoma
  Essential hypertension
  High blood pressure
  Myocardial infarction
  Neoplasm
  Glomuvenous malformation
  Lateral meningocele syndrome
  Leiomyoma
  Limb-mammary syndrome
  Uterine fibroids
  Wilms tumor
• UniProt ID: SMTN_HUMAN
• PDB ID: 2D87
• Pfam ID: PF00307 ; PF12510
• Sequence:
  MADEALAGLDEGALRKLLEVTADLAERRRIRSAIRELQRQELEREEEALASKRFRAERQD
  NKENWLHSQQREAEQRAALARLAGQLESMNDVEELTALLRSAGEYEERKLIRAAIRRVRA
  QEIEAATLAGRLYSGRPNSGSREDSKGLAAHRLEQCEVPEREEQEQQAEVSKPTPTPEGT
  SQDVTTVTLLLRAPPGSTSSSPASPSSSPTPASPEPPLEPAEAQCLTAEVPGSPEPPPSP
  PKTTSPEPQESPTLPSTEGQVVNKLLSGPKETPAAQSPTRGPSDTKRADVAGPRPCQRSL
  SVLSPRQPAQNRESTPLASGPSSFQRAGSVRDRVHKFTSDSPMAARLQDGTPQAALSPLT
  PARLLGPSLTSTTPASSSSGSSSRGPSDTSSRFSKEQRGVAQPLAQLRSCPQEEGPRGRG
  LAARPLENRAGGPVARSEEPGAPLPVAVGTAEPGGSMKTTFTIEIKDGRGQASTGRVLLP
  TGNQRAELTLGLRAPPTLLSTSSGGKSTITRVNSPGTLARLGSVTHVTSFSHAPPSSRGG
  CSIKMEAEPAEPLAAAVEAANGAEQTRVNKAPEGRSPLSAEELMTIEDEGVLDKMLDQST
  DFEERKLIRAALRELRQRKRDQRDKERERRLQEARGRPGEGRGNTATETTTRHSQRAADG
  SAVSTVTKTERLVHSNDGTRTARTTTVESSFVRRSENGSGSTMMQTKTFSSSSSSKKMGS
  IFDREDQASPRAGSLAALEKRQAEKKKELMKAQSLPKTSASQARKAMIEKLEKEGAAGSP
  GGPRAAVQRSTSFGVPNANSIKQMLLDWCRAKTRGYEHVDIQNFSSSWSDGMAFCALVHN
  FFPEAFDYGQLSPQNRRQNFEVAFSSAEMLVDCVPLVEVDDMMIMGKKPDPKCVFTYVQS
  LYNHLRRHELRLRGKNV
• Function: Structural protein of the cytoskeleton.
• Tissue Specificity: Smooth muscle; contractile or vascular (for the long form).

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebral infarction	DISR1WNP	Definitive	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Biomarker	[2]
Esophageal adenocarcinoma	DISODWFP	Strong	Biomarker	[3]
Essential hypertension	DIS7WI98	Strong	Genetic Variation	[4]
High blood pressure	DISY2OHH	Strong	Biomarker	[4]
Myocardial infarction	DIS655KI	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Glomuvenous malformation	DIS5UNDD	Limited	Altered Expression	[6]
Lateral meningocele syndrome	DISG74RP	Limited	Biomarker	[7]
Leiomyoma	DISLDDFN	Limited	Biomarker	[7]
Limb-mammary syndrome	DIS7H4FP	Limited	Biomarker	[7]
Uterine fibroids	DISBZRMJ	Limited	Biomarker	[7]
Wilms tumor	DISB6T16	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Smoothelin (SMTN).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Smoothelin (SMTN).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Smoothelin (SMTN).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Smoothelin (SMTN).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Smoothelin (SMTN).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Smoothelin (SMTN).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Smoothelin (SMTN).	[14]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Smoothelin (SMTN).	[15]
Selenium	DM25CGV	Approved	Selenium increases the expression of Smoothelin (SMTN).	[16]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Smoothelin (SMTN).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Smoothelin (SMTN).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Smoothelin (SMTN).	[16]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Smoothelin (SMTN).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Smoothelin (SMTN).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Smoothelin (SMTN).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Smoothelin (SMTN).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Smoothelin (SMTN).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Smoothelin (SMTN).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Smoothelin (SMTN).	[23]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Smoothelin (SMTN).	[23]

References

• [1] Association of the smoothelin (SMTN) gene with cerebral infarction in men: a haplotype-based case-control study.Vasc Med. 2012 Oct;17(5):317-25. doi: 10.1177/1358863X12453938.
• [2] Diagnostic value of smoothelin and vimentin in differentiating muscularis propria from muscularis mucosa of bladder carcinoma.Int J Biol Markers. 2017 Jul 24;32(3):e305-e312. doi: 10.5301/jbm.5000252.
• [3] Value of histomorphometric tumour thickness and smoothelin for conventional m-classification in early oesophageal adenocarcinoma.World J Gastrointest Oncol. 2017 Nov 15;9(11):444-451. doi: 10.4251/wjgo.v9.i11.444.
• [4] Haplotype of smoothelin gene associated with essential hypertension.Hereditas. 2012 Oct;149(5):178-85. doi: 10.1111/j.1601-5223.2012.02242.x. Epub 2012 Oct 18.
• [5] A haplotype of the SMTN gene associated with myocardial infarction in Japanese women.Genet Test Mol Biomarkers. 2012 Sep;16(9):1019-26. doi: 10.1089/gtmb.2012.0034.
• [6] Smoothelin and WT-1 expression in glomus tumors and glomuvenous malformations.Histol Histopathol. 2017 Feb;32(2):153-160. doi: 10.14670/HH-11-782. Epub 2016 May 17.
• [7] The Use of Smoothelin and Other Antibodies in the Diagnosis of Uterine and Soft Tissue Smooth Muscle Tumors.Appl Immunohistochem Mol Morphol. 2019 May/Jun;27(5):386-391. doi: 10.1097/PAI.0000000000000619.
• [8] Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicol In Vitro. 2009 Apr;23(3):486-99.
• [9] 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.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [13] 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.
• [14] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [15] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [16] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [17] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [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] 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.
• [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] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [25] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.