Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI1OBLN)

• DOT Name: Protein THEMIS2 (THEMIS2)
• Synonyms: Induced by contact to basement membrane 1 protein; Protein ICB-1; Thymocyte-expressed molecule involved in selection protein 2
• Gene Name: THEMIS2
• Related Disease:
  Advanced cancer
  Breast neoplasm
  Endometrium adenocarcinoma
  Epithelial ovarian cancer
  Glomerulonephritis
  Neoplasm
  Nephritis
  Ovarian cancer
  Ovarian neoplasm
  Breast cancer
  Breast carcinoma
  Endometrial cancer
  Endometrial carcinoma
• UniProt ID: THMS2_HUMAN
• Pfam ID: PF12736
• Sequence:
  MEPVPLQDFVRALDPASLPRVLRVCSGVYFEGSIYEISGNECCLSTGDLIKVTQVRLQKV
  VCENPKTSQTMELAPNFQGYFTPLNTPQSYETLEELVSATTQSSKQLPTCFMSTHRIVTE
  GRVVTEDQLLMLEAVVMHLGIRSARCVLGMEGQQVILHLPLSQKGPFWTWEPSAPRTLLQ
  VLQDPALKDLVLTCPTLPWHSLILRPQYEIQAIMHMRRTIVKIPSTLEVDVEDVTASSRH
  VHFIKPLLLSEVLAWEGPFPLSMEILEVPEGRPIFLSPWVGSLQKGQRLCVYGLASPPWR
  VLASSKGRKVPRHFLVSGGYQGKLRRRPREFPTAYDLLGAFQPGRPLRVVATKDCEGERE
  ENPEFTSLAVGDRLEVLGPGQAHGAQGSDVDVLVCQRLSDQAGEDEEEECKEEAESPERV
  LLPFHFPGSFVEEMSDSRRYSLADLTAQFSLPCEVKVVAKDTSHPTDPLTSFLGLRLEEK
  ITEPFLVVSLDSEPGMCFEIPPRWLDLTVVKAKGQPDLPEGSLPIATVEELTDTFYYRLR
  KLPACEIQAPPPRPPKNQGLSKQRRHSSEGGVKSSQVLGLQQHARLPKPKAKTLPEFIKD
  GSSTYSKIPAHRKGHRPAKPQRQDLDDDEHDYEEILEQFQKTI
• Function: May constitute a control point in macrophage inflammatory response, promoting LPS-induced TLR4-mediated TNF production. Determines the threshold for activation of B cells by low-affinity and low-avidity ligands via PLCG2 activation and its downstream pathways.
• Tissue Specificity: Expressed in different endometrial adenocarcinoma cell lines and various other cell lines apart from the prostate cell line LNCaP and the ovarian cancer cell line BG1.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Therapeutic	[1]
Endometrium adenocarcinoma	DISY6744	Strong	Altered Expression	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[3]
Glomerulonephritis	DISPZIQ3	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Nephritis	DISQZQ70	Strong	Biomarker	[6]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[3]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Limited	Biomarker	[5]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[5]
Endometrial cancer	DISW0LMR	Limited	Biomarker	[7]
Endometrial carcinoma	DISXR5CY	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Protein THEMIS2 (THEMIS2).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein THEMIS2 (THEMIS2).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein THEMIS2 (THEMIS2).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein THEMIS2 (THEMIS2).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Protein THEMIS2 (THEMIS2).	[12]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Protein THEMIS2 (THEMIS2).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein THEMIS2 (THEMIS2).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein THEMIS2 (THEMIS2).	[15]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Protein THEMIS2 (THEMIS2).	[9]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 increases the expression of Protein THEMIS2 (THEMIS2).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein THEMIS2 (THEMIS2).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Protein THEMIS2 (THEMIS2).	[19]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Protein THEMIS2 (THEMIS2).	[20]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Protein THEMIS2 (THEMIS2).	[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 affects the methylation of Protein THEMIS2 (THEMIS2).	[17]

References

• [1] Knockdown of ICB-1 gene enhanced estrogen responsiveness of ovarian and breast cancer cells.Endocr Relat Cancer. 2010 Feb 18;17(1):147-57. doi: 10.1677/ERC-09-0095. Print 2010 Mar.
• [2] Icb-1 Gene expression is elevated in human endometrial adenocarcinoma and is closely associated with HER2 expression.Cancer Invest. 2010 Nov;28(9):904-9. doi: 10.3109/07357907.2010.483511.
• [3] Icb-1 gene polymorphism rs1467465 is associated with susceptibility to ovarian cancer.J Ovarian Res. 2014 Apr 23;7:42. doi: 10.1186/1757-2215-7-42. eCollection 2014.
• [4] Neutrophil FcRIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases.J Clin Invest. 2017 Oct 2;127(10):3810-3826. doi: 10.1172/JCI94039. Epub 2017 Sep 11.
• [5] Network analysis of icb-1 gene function in human breast cancer cells.J Cell Biochem. 2012 Sep;113(9):2979-88. doi: 10.1002/jcb.24175.
• [6] Dependence of Glomerulonephritis Induction on Novel Intraglomerular Alternatively Activated Bone Marrow-Derived Macrophages and Mac-1 and PD-L1 in Lupus-Prone NZM2328 Mice.J Immunol. 2017 Apr 1;198(7):2589-2601. doi: 10.4049/jimmunol.1601565. Epub 2017 Feb 20.
• [7] Silencing of the icb-1 gene inhibits the induction of differentiation-associated genes by vitamin D3 and all-trans retinoic acid in gynecological cancer cells.Int J Mol Med. 2011 Jul;28(1):121-7. doi: 10.3892/ijmm.2011.663. Epub 2011 Mar 31.
• [8] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [9] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [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] Quantitative proteomic analysis of HepG2 cells treated with quercetin suggests IQGAP1 involved in quercetin-induced regulation of cell proliferation and migration. OMICS. 2009 Apr;13(2):93-103. doi: 10.1089/omi.2008.0075.
• [13] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [16] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [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] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [19] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [20] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [21] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.