Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1XMRIM)

• DOT Name: Tsukushi (TSKU)
• Synonyms: E2-induced gene 4 protein; Leucine-rich repeat-containing protein 54
• Gene Name: TSKU
• Related Disease:
  Anxiety
  Anxiety disorder
  Colorectal carcinoma
  Depression
  Osteoarthritis
  Systemic sclerosis
  Ankylosing spondylitis
  Stroke
• UniProt ID: TSK_HUMAN
• Pfam ID: PF00560 ; PF13855
• Sequence:
  MPWPLLLLLAVSGAQTTRPCFPGCQCEVETFGLFDSFSLTRVDCSGLGPHIMPVPIPLDT
  AHLDLSSNRLEMVNESVLAGPGYTTLAGLDLSHNLLTSISPTAFSRLRYLESLDLSHNGL
  TALPAESFTSSPLSDVNLSHNQLREVSVSAFTTHSQGRALHVDLSHNLIHRLVPHPTRAG
  LPAPTIQSLNLAWNRLHAVPNLRDLPLRYLSLDGNPLAVIGPGAFAGLGGLTHLSLASLQ
  RLPELAPSGFRELPGLQVLDLSGNPKLNWAGAEVFSGLSSLQELDLSGTNLVPLPEALLL
  HLPALQSVSVGQDVRCRRLVREGTYPRRPGSSPKVALHCVDTRDSAARGPTIL
• Function: Contributes to various developmental events and other processes such as wound healing and cholesterol homeostasis through its interactions with multiple signaling pathways. Wnt signaling inhibitor which competes with WNT2B for binding to Wnt receptor FZD4 and represses WNT2B-dependent development of the peripheral eye. Plays a role in regulating the hair cycle by controlling TGFB1 signaling. Required for the development of the anterior commissure in the brain by inhibiting neurite outgrowth. Essential for terminal differentiation of hippocampal neural stem cells. Plays a role in regulating bone elongation and bone mass by modulating growth plate chondrocyte function and overall body size. Required for development of the inner ear through its involvement in stereocilia formation in inner hair cells. Facilitates wound healing by inhibiting secretion of TGFB1 from macrophages which prevents myofibroblast differentiation, maintaining inflammatory cell quiescence. Plays a role in cholesterol homeostasis by reducing circulating high-density lipoprotein cholesterol, lowering cholesterol efflux capacity and decreasing cholesterol-to-bile acid conversion in the liver. In one study, shown to negatively regulate sympathetic innervation in brown fat, leading to reduced energy expenditure. In another study, shown not to affect brown fat thermogenic capacity, body weight gain or glucose homeostasis.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anxiety	DISIJDBA	Strong	Genetic Variation	[1]
Anxiety disorder	DISBI2BT	Strong	Genetic Variation	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
Depression	DIS3XJ69	Strong	Genetic Variation	[1]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[3]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[4]
Ankylosing spondylitis	DISRC6IR	Limited	Biomarker	[5]
Stroke	DISX6UHX	Limited	Biomarker	[6]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Tsukushi (TSKU) decreases the response to substance of Arsenic trioxide.	[24]

19 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 Tsukushi (TSKU).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tsukushi (TSKU).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tsukushi (TSKU).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tsukushi (TSKU).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Tsukushi (TSKU).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tsukushi (TSKU).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Tsukushi (TSKU).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Tsukushi (TSKU).	[14]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Tsukushi (TSKU).	[14]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Tsukushi (TSKU).	[15]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Tsukushi (TSKU).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Tsukushi (TSKU).	[17]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Tsukushi (TSKU).	[18]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Tsukushi (TSKU).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Tsukushi (TSKU).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tsukushi (TSKU).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Tsukushi (TSKU).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Tsukushi (TSKU).	[19]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Tsukushi (TSKU).	[23]

References

• [1] Widespread pain in axial spondyloarthritis: clinical importance and gender differences.Arthritis Res Ther. 2018 Jul 27;20(1):156. doi: 10.1186/s13075-018-1626-8.
• [2] MicroRNA-mRNA interaction network using TSK-type recurrent neural fuzzy network.Gene. 2013 Feb 25;515(2):385-90. doi: 10.1016/j.gene.2012.12.063. Epub 2012 Dec 20.
• [3] Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data. Nat Genet. 2019 Feb;51(2):230-236.
• [4] Suppressive Regulation by MFG-E8 of Latent Transforming Growth Factor -Induced Fibrosis via Binding to v Integrin: Significance in the Pathogenesis of Fibrosis in Systemic Sclerosis.Arthritis Rheumatol. 2019 Feb;71(2):302-314. doi: 10.1002/art.40701. Epub 2019 Jan 4.
• [5] Activity Limitations in Patients with Axial Spondyloarthritis: A Role for Fear of Movement and (Re)injury Beliefs.J Rheumatol. 2018 Mar;45(3):357-366. doi: 10.3899/jrheum.170318. Epub 2017 Nov 15.
• [6] Cardiovascular Drift during Training for Fitness in Patients with Metabolic Syndrome.Med Sci Sports Exerc. 2017 Mar;49(3):518-526. doi: 10.1249/MSS.0000000000001139.
• [7] 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.
• [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] 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.
• [10] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Identification of estrogen-responsive genes by complementary deoxyribonucleic acid microarray and characterization of a novel early estrogen-induced gene: EEIG1. Mol Endocrinol. 2004 Feb;18(2):402-11. doi: 10.1210/me.2003-0202. Epub 2003 Nov 6.
• [13] 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.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [16] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [19] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [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] 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.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [24] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.