Details of Drug Off-Target (DOT)

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

• DOT Name: Transmembrane protein 98 (TMEM98)
• Synonyms: Protein TADA1
• Gene Name: TMEM98
• Related Disease:
  Hepatocellular carcinoma
  Late-onset Parkinson disease
  Nanophthalmos 4
  Neoplasm
  Panic disorder
  Microphthalmia
  Nanophthalmia
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
• UniProt ID: TMM98_HUMAN
• Sequence:
  METVVIVAIGVLATIFLASFAALVLVCRQRYCRPRDLLQRYDSKPIVDLIGAMETQSEPS
  ELELDDVVITNPHIEAILENEDWIEDASGLMSHCIAILKICHTLTEKLVAMTMGSGAKMK
  TSASVSDIIVVAKRISPRVDDVVKSMYPPLDPKLLDARTTALLLSVSHLVLVTRNACHLT
  GGLDWIDQSLSAAEEHLEVLREAALASEPDKGLPGPEGFLQEQSAI
• Function: Functions as a negative regulator of MYRF in oligodendrocyte differentiation and myelination. Interacts with the C-terminal of MYRF inhibiting MYRF self-cleavage and N-fragment nuclear translocation. The secreted form promotes differentiation of T helper 1 cells (Th1).
• Tissue Specificity: Widely expressed with high expression in the ovary, pancreas and prostate . Expressed in the eye, particularly in corneal endothelium, iris, ciliary body, sclera, optic nerve, optic nerve head, and retina . Expressed by activated peripheral blood mononuclear cells .

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[1]
Late-onset Parkinson disease	DIS9IOUI	Strong	Biomarker	[2]
Nanophthalmos 4	DIS34PZB	Strong	Autosomal dominant	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Panic disorder	DISD3VNY	Strong	Biomarker	[2]
Microphthalmia	DISGEBES	moderate	Genetic Variation	[4]
Nanophthalmia	DISIULDO	Supportive	Autosomal dominant	[3]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[5]
Arteriosclerosis	DISK5QGC	Limited	Biomarker	[6]
Atherosclerosis	DISMN9J3	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Transmembrane protein 98 (TMEM98).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transmembrane protein 98 (TMEM98).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transmembrane protein 98 (TMEM98).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transmembrane protein 98 (TMEM98).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Transmembrane protein 98 (TMEM98).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Transmembrane protein 98 (TMEM98).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transmembrane protein 98 (TMEM98).	[13]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Transmembrane protein 98 (TMEM98).	[14]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Transmembrane protein 98 (TMEM98).	[15]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Transmembrane protein 98 (TMEM98).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transmembrane protein 98 (TMEM98).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Transmembrane protein 98 (TMEM98).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Transmembrane protein 98 (TMEM98).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Transmembrane protein 98 (TMEM98).	[21]

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 decreases the methylation of Transmembrane protein 98 (TMEM98).	[17]

References

• [1] Identification of transmembrane protein 98 as a novel chemoresistance-conferring gene in hepatocellular carcinoma.Mol Cancer Ther. 2014 May;13(5):1285-97. doi: 10.1158/1535-7163.MCT-13-0806. Epub 2014 Mar 7.
• [2] Are TMEM genes potential candidate genes for panic disorder?.Psychiatr Genet. 2014 Feb;24(1):37-41. doi: 10.1097/YPG.0000000000000022.
• [3] Mutation in TMEM98 in a large white kindred with autosomal dominant nanophthalmos linked to 17p12-q12. JAMA Ophthalmol. 2014 Aug;132(8):970-7. doi: 10.1001/jamaophthalmol.2014.946.
• [4] Missense Mutations in the Human Nanophthalmos Gene TMEM98 Cause Retinal Defects in the Mouse.Invest Ophthalmol Vis Sci. 2019 Jul 1;60(8):2875-2887. doi: 10.1167/iovs.18-25954.
• [5] siRNA-TMEM98 inhibits the invasion and migration of lung cancer cells.Int J Clin Exp Pathol. 2015 Dec 1;8(12):15661-9. eCollection 2015.
• [6] Inhibition of IL-8-mediated endothelial adhesion, VSMCs proliferation and migration by siRNA-TMEM98 suggests TMEM98's emerging role in atherosclerosis.Oncotarget. 2017 Sep 30;8(50):88043-88058. doi: 10.18632/oncotarget.21408. eCollection 2017 Oct 20.
• [7] 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.
• [8] 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.
• [9] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [13] 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.
• [14] 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.
• [15] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [16] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [17] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [18] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [19] 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.
• [20] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [21] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.