Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG5KEV8)

• DOT Name: Tectonic-1 (TCTN1)
• Gene Name: TCTN1
• Related Disease:
  Holoprosencephaly
  Adult glioblastoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Gastric cancer
  Glioblastoma multiforme
  Glioma
  Joubert syndrome 1
  Joubert syndrome 13
  Meckel syndrome, type 1
  Neoplasm
  Non-small-cell lung cancer
  Orofaciodigital syndrome
  Orofaciodigital syndrome type 6
  Pancreatic cancer
  Stomach cancer
  Joubert syndrome
  Meckel syndrome
  Intellectual disability
  Prostate cancer
  Prostate carcinoma
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
• UniProt ID: TECT1_HUMAN
• Pfam ID: PF07773
• Sequence:
  MRPRGLPPLLVVLLGCWASVSAQTDATPAVTTEGLNSTEAALATFGTFPSTRPPGTPRAP
  GPSSGPRPTPVTDVAVLCVCDLSPAQCDINCCCDPDCSSVDFSVFSACSVPVVTGDSQFC
  SQKAVIYSLNFTANPPQRVFELVDQINPSIFCIHITNYKPALSFINPEVPDENNFDTLMK
  TSDGFTLNAESYVSFTTKLDIPTAAKYEYGVPLQTSDSFLRFPSSLTSSLCTDNNPAAFL
  VNQAVKCTRKINLEQCEEIEALSMAFYSSPEILRVPDSRKKVPITVQSIVIQSLNKTLTR
  REDTDVLQPTLVNAGHFSLCVNVVLEVKYSLTYTDAGEVTKADLSFVLGTVSSVVVPLQQ
  KFEIHFLQENTQPVPLSGNPGYVVGLPLAAGFQPHKGSGIIQTTNRYGQLTILHSTTEQD
  CLALEGVRTPVLFGYTMQSGCKLRLTGALPCQLVAQKVKSLLWGQGFPDYVAPFGNSQAQ
  DMLDWVPIHFITQSFNRKDSCQLPGALVIEVKWTKYGSLLNPQAKIVNVTANLISSSFPE
  ANSGNERTILISTAVTFVDVSAPAEAGFRAPPAINARLPFNFFFPFV
• Function: Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. Regulator of Hedgehog (Hh), required for both activation and inhibition of the Hh pathway in the patterning of the neural tube. During neural tube development, it is required for formation of the most ventral cell types and for full Hh pathway activation. Functions in Hh signal transduction to fully activate the pathway in the presence of high Hh levels and to repress the pathway in the absence of Hh signals. Modulates Hh signal transduction downstream of SMO and RAB23.
• Reactome Pathway: Anchoring of the basal body to the plasma membrane (R-HSA-5620912)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Holoprosencephaly	DISR35EC	Definitive	Genetic Variation	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[5]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Glioma	DIS5RPEH	Strong	Biomarker	[6]
Joubert syndrome 1	DISC9Q82	Strong	GermlineCausalMutation	[7]
Joubert syndrome 13	DIS2KVQH	Strong	Autosomal recessive	[8]
Meckel syndrome, type 1	DIS4YWZU	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Orofaciodigital syndrome	DISSB296	Strong	Biomarker	[9]
Orofaciodigital syndrome type 6	DISQY7K4	Strong	Genetic Variation	[9]
Pancreatic cancer	DISJC981	Strong	Biomarker	[11]
Stomach cancer	DISKIJSX	Strong	Biomarker	[5]
Joubert syndrome	DIS7P5CO	Supportive	Autosomal recessive	[7]
Meckel syndrome	DISXPHOY	Supportive	Autosomal recessive	[9]
Intellectual disability	DISMBNXP	Limited	Biomarker	[12]
Prostate cancer	DISF190Y	Limited	Altered Expression	[13]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[13]
Thyroid cancer	DIS3VLDH	Limited	Biomarker	[11]
Thyroid gland carcinoma	DISMNGZ0	Limited	Biomarker	[11]
Thyroid tumor	DISLVKMD	Limited	Biomarker	[11]

11 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 Tectonic-1 (TCTN1).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tectonic-1 (TCTN1).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tectonic-1 (TCTN1).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tectonic-1 (TCTN1).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Tectonic-1 (TCTN1).	[18]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Tectonic-1 (TCTN1).	[19]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Tectonic-1 (TCTN1).	[20]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Tectonic-1 (TCTN1).	[21]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Tectonic-1 (TCTN1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Tectonic-1 (TCTN1).	[23]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Tectonic-1 (TCTN1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Tectonic-1 (TCTN1).	[22]

References

• [1] Three Tctn proteins are functionally conserved in the regulation of neural tube patterning and Gli3 processing but not ciliogenesis and Hedgehog signaling in the mouse.Dev Biol. 2017 Oct 1;430(1):156-165. doi: 10.1016/j.ydbio.2017.08.003. Epub 2017 Aug 8.
• [2] Expression and prognostic significance of TCTN1 in human glioblastoma.J Transl Med. 2014 Oct 11;12:288. doi: 10.1186/s12967-014-0288-9.
• [3] Knockdown of TCTN1 Strongly Decreases Growth of Human Colon Cancer Cells.Med Sci Monit. 2017 Jan 26;23:452-461. doi: 10.12659/msm.899595.
• [4] MiR-216a-5p targets TCTN1 to inhibit cell proliferation and induce apoptosis in esophageal squamous cell carcinoma.Cell Mol Biol Lett. 2019 Jun 28;24:46. doi: 10.1186/s11658-019-0166-9. eCollection 2019.
• [5] Tectonic 1 accelerates gastric cancer cell proliferation and cell cycle progression in vitro.Mol Med Rep. 2015 Oct;12(4):5897-902. doi: 10.3892/mmr.2015.4177. Epub 2015 Aug 5.
• [6] Lentivirus-Mediated Knockdown of TCTN1 Inhibits Glioma Cell Proliferation.Appl Biochem Biotechnol. 2015 May;176(1):13-21. doi: 10.1007/s12010-015-1498-1. Epub 2015 Mar 4.
• [7] A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nat Genet. 2011 Jul 3;43(8):776-84. doi: 10.1038/ng.891.
• [8] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [9] Expanding the allelic disorders linked to TCTN1 to include Varadi syndrome (Orofaciodigital syndrome type VI). Am J Med Genet A. 2017 Sep;173(9):2439-2441. doi: 10.1002/ajmg.a.38336. Epub 2017 Jun 20.
• [10] MiR-1256 suppresses proliferation and migration of non-small cell lung cancer via regulating TCTN1.Oncol Lett. 2018 Aug;16(2):1708-1714. doi: 10.3892/ol.2018.8794. Epub 2018 May 24.
• [11] Silencing of TCTN1 inhibits proliferation, induces cell cycle arrest and apoptosis in human thyroid cancer.Exp Ther Med. 2017 Oct;14(4):3720-3726. doi: 10.3892/etm.2017.4940. Epub 2017 Aug 16.
• [12] Molecular characterization of Joubert syndrome in Saudi Arabia. Hum Mutat. 2012 Oct;33(10):1423-8. doi: 10.1002/humu.22134. Epub 2012 Jul 11.
• [13] Tectonic? contributes to the growth and migration of prostate cancer cells invitro.Int J Mol Med. 2015 Oct;36(4):931-8. doi: 10.3892/ijmm.2015.2313. Epub 2015 Aug 14.
• [14] 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.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [20] 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.
• [21] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [22] 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.
• [23] 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.
• [24] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.