Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH6M3CH)

• DOT Name: Tomoregulin-1 (TMEFF1)
• Synonyms: TR-1; H7365; Transmembrane protein with EGF-like and one follistatin-like domain
• Gene Name: TMEFF1
• Related Disease:
  Advanced cancer
  Brain cancer
  Brain neoplasm
  Breast cancer
  Epithelial ovarian cancer
  Neoplasm
  Testicular cancer
• UniProt ID: TEFF1_HUMAN
• Pfam ID: PF07648
• Sequence:
  MGAAAAEAPLRLPAAPPLAFCCYTSVLLLFAFSLPGSRASNQPPGGGGGSGGDCPGGKGK
  SINCSELNVRESDVRVCDESSCKYGGVCKEDGDGLKCACQFQCHTNYIPVCGSNGDTYQN
  ECFLRRAACKHQKEITVIARGPCYSDNGSGSGEGEEEGSGAEVHRKHSKCGPCKYKAECD
  EDAENVGCVCNIDCSGYSFNPVCASDGSSYNNPCFVREASCIKQEQIDIRHLGHCTDTDD
  TSLLGKKDDGLQYRPDVKDASDQREDVYIGNHMPCPENLNGYCIHGKCEFIYSTQKASCR
  CESGYTGQHCEKTDFSILYVVPSRQKLTHVLIAAIIGAVQIAIIVAIVMCITRKCPKNNR
  GRRQKQNLGHFTSDTSSRMV
• Function: May inhibit NODAL and BMP signaling during neural patterning. May be a tumor suppressor in brain cancers.
• Tissue Specificity: Expressed predominantly in brain, and at lower levels in heart, placenta and skeletal muscle. Down-regulated in brain tumors as compared to control brain tissues.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Brain cancer	DISBKFB7	Strong	Biomarker	[1]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Testicular cancer	DIS6HNYO	Strong	Altered Expression	[4]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Tomoregulin-1 (TMEFF1) affects the response to substance of Methotrexate.	[17]
Cyclophosphamide	DM4O2Z7	Approved	Tomoregulin-1 (TMEFF1) affects the response to substance of Cyclophosphamide.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Tomoregulin-1 (TMEFF1).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Tomoregulin-1 (TMEFF1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tomoregulin-1 (TMEFF1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Tomoregulin-1 (TMEFF1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Tomoregulin-1 (TMEFF1).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tomoregulin-1 (TMEFF1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Tomoregulin-1 (TMEFF1).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Tomoregulin-1 (TMEFF1).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Tomoregulin-1 (TMEFF1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Tomoregulin-1 (TMEFF1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Tomoregulin-1 (TMEFF1).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Tomoregulin-1 (TMEFF1).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Tomoregulin-1 (TMEFF1).	[16]

References

• [1] TMEFF1 and brain tumors.Oncogene. 2003 May 8;22(18):2723-7. doi: 10.1038/sj.onc.1206351.
• [2] TMEFF1 overexpression and its mechanism for tumor promotion in ovarian cancer.Cancer Manag Res. 2019 Jan 17;11:839-855. doi: 10.2147/CMAR.S186080. eCollection 2019.
• [3] Lack of transforming growth factor- signaling promotes collective cancer cell invasion through tumor-stromal crosstalk.Breast Cancer Res. 2012 Jul 2;14(4):R98. doi: 10.1186/bcr3217.
• [4] Cancer-testis antigens as biomarkers for Merkel cell carcinoma: Pitfalls and opportunities.J Cutan Pathol. 2019 Oct;46(10):748-752. doi: 10.1111/cup.13528. Epub 2019 Jul 11.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 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.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.
• [14] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.