Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1RWIH7)

• DOT Name: Membrane protein BRI3 (BRI3)
• Synonyms: Brain protein I3; pRGR2
• Gene Name: BRI3
• Related Disease:
  Alzheimer disease
  Colon cancer
  Colon carcinoma
  Dementia
  Breast cancer
  Breast carcinoma
  Hepatocellular carcinoma
  Neuroendocrine neoplasm
• UniProt ID: BRI3_HUMAN
• Pfam ID: PF10164
• Sequence:
  MDHKPLLQERPPAYNLEAGQGDYACGPHGYGAIPAAPPPPPYPYLVTGIPTHHPRVYNIH
  SRTVTRYPANSIVVVGGCPVCRVGVLEDCFTFLGIFLAIILFPFGFICCFALRKRRCPNC
  GATFA
• Function: Participates in tumor necrosis factor-alpha (TNF)-induced cell death. May be a target of Wnt/beta-catenin signaling in the liver.
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Colon cancer	DISVC52G	Strong	Biomarker	[2]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[2]
Dementia	DISXL1WY	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Limited	Biomarker	[4]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[5]
Neuroendocrine neoplasm	DISNPLOO	Limited	Biomarker	[6]

15 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 Membrane protein BRI3 (BRI3).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Membrane protein BRI3 (BRI3).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Membrane protein BRI3 (BRI3).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Membrane protein BRI3 (BRI3).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Membrane protein BRI3 (BRI3).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Membrane protein BRI3 (BRI3).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Membrane protein BRI3 (BRI3).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Membrane protein BRI3 (BRI3).	[14]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the expression of Membrane protein BRI3 (BRI3).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Membrane protein BRI3 (BRI3).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Membrane protein BRI3 (BRI3).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Membrane protein BRI3 (BRI3).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Membrane protein BRI3 (BRI3).	[20]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Membrane protein BRI3 (BRI3).	[21]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone affects the splicing of Membrane protein BRI3 (BRI3).	[22]

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 Membrane protein BRI3 (BRI3).	[16]

References

• [1] BRI3 inhibits amyloid precursor protein processing in a mechanistically distinct manner from its homologue dementia gene BRI2.J Biol Chem. 2009 Jun 5;284(23):15815-25. doi: 10.1074/jbc.M109.006403. Epub 2009 Apr 14.
• [2] A gene signature of 8 genes could identify the risk of recurrence and progression in Dukes' B colon cancer patients.Oncol Rep. 2007 May;17(5):1089-94.
• [3] BRI2 and BRI3 are functionally distinct phosphoproteins.Cell Signal. 2016 Jan;28(1):130-44. doi: 10.1016/j.cellsig.2015.10.012. Epub 2015 Oct 26.
• [4] Nifedipine promotes the proliferation and migration of breast cancer cells.PLoS One. 2014 Dec 1;9(12):e113649. doi: 10.1371/journal.pone.0113649. eCollection 2014.
• [5] Identification of IFITM3 and MGAT1 as novel interaction partners of BRI3 by yeast two-hybrid screening.Turk J Biol. 2018 Dec 10;42(6):463-470. doi: 10.3906/biy-1805-47. eCollection 2018.
• [6] MEG3 Suppresses Human Pancreatic Neuroendocrine Tumor Cells Growth and Metastasis by Down-Regulation of Mir-183.Cell Physiol Biochem. 2017;44(1):345-356. doi: 10.1159/000484906. Epub 2017 Nov 13.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] 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.
• [14] 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.
• [15] Screening autism-associated environmental factors in differentiating human neural progenitors with fractional factorial design-based transcriptomics. Sci Rep. 2023 Jun 29;13(1):10519. doi: 10.1038/s41598-023-37488-0.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [22] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.