Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYRKIJ1)

• DOT Name: Protein bicaudal C homolog 1 (BICC1)
• Synonyms: Bic-C
• Gene Name: BICC1
• Related Disease:
  Autosomal dominant polycystic kidney disease
  Autosomal recessive polycystic kidney disease
  Cardiovascular disease
  Ciliopathy
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Depression
  Glaucoma/ocular hypertension
  Mood disorder
  Nephropathy
  Non-insulin dependent diabetes
  Open-angle glaucoma
  Polycystic kidney disease
  Type-1/2 diabetes
  Major depressive disorder
  Bipolar depression
  Bipolar disorder
  Myopia
  Renal dysplasia, cystic, susceptibility to
• UniProt ID: BICC1_HUMAN
• PDB ID: 4RQM; 4RQN; 6GY4
• Pfam ID: PF00013 ; PF00536
• Sequence:
  MAAQGEPGYLAAQSDPGSNSERSTDSPVPGSEDDLVAGATLHSPEWSEERFRVDRKKLEA
  MLQAAAEGKGRSGEDFFQKIMEETNTQIAWPSKLKIGAKSKKDPHIKVSGKKEDVKEAKE
  MIMSVLDTKSNRVTLKMDVSHTEHSHVIGKGGNNIKKVMEETGCHIHFPDSNRNNQAEKS
  NQVSIAGQPAGVESARVRIRELLPLVLMFELPIAGILQPVPDPNSPSIQHISQTYNISVS
  FKQRSRMYGATVIVRGSQNNTSAVKEGTAMLLEHLAGSLASAIPVSTQLDIAAQHHLFMM
  GRNGSNIKHIMQRTGAQIHFPDPSNPQKKSTVYLQGTIESVCLARQYLMGCLPLVLMFDM
  KEEIEVDPQFIAQLMEQLDVFISIKPKPKQPSKSVIVKSVERNALNMYEARKCLLGLESS
  GVTIATSPSPASCPAGLACPSLDILASAGLGLTGLGLLGPTTLSLNTSTTPNSLLNALNS
  SVSPLQSPSSGTPSPTLWAPPLANTSSATGFSAIPHLMIPSTAQATLTNILLSGVPTYGH
  TAPSPPPGLTPVDVHINSMQTEGKKISAALNGHAQSPDIKYGAISTSSLGEKVLSANHGD
  PSIQTSGSEQTSPKSSPTEGCNDAFVEVGMPRSPSHSGNAGDLKQMMCPSKVSCAKRQTV
  ELLQGTKNSHLHSTDRLLSDPELSATESPLADKKAPGSERAAERAAAAQQNSERAHLAPR
  SSYVNMQAFDYEQKKLLATKAMLKKPVVTEVRTPTNTWSGLGFSKSMPAETIKELRRANH
  VSYKPTMTTTYEGSSMSLSRSNSREHLGGGSESDNWRDRNGIGPGSHSEFAASIGSPKRK
  QNKSTEHYLSSSNYMDCISSLTGSNGCNLNSSFKGSDLPELFSKLGLGKYTDVFQQQEID
  LQTFLTLTDQDLKELGITTFGARRKMLLAISELNKNRRKLFESPNARTSFLEGGASGRLP
  RQYHSDIASVSGRW
• Function: Putative RNA-binding protein. Acts as a negative regulator of Wnt signaling. May be involved in regulating gene expression during embryonic development.

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant polycystic kidney disease	DISBHWUI	Definitive	Genetic Variation	[1]
Autosomal recessive polycystic kidney disease	DISPUS40	Strong	Biomarker	[2]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[3]
Ciliopathy	DIS10G4I	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Strong	Genetic Variation	[5]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[5]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[5]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[5]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[5]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[5]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[5]
Depression	DIS3XJ69	Strong	Biomarker	[6]
Glaucoma/ocular hypertension	DISLBXBY	Strong	Genetic Variation	[7]
Mood disorder	DISLVMWO	Strong	Biomarker	[8]
Nephropathy	DISXWP4P	Strong	Genetic Variation	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[9]
Open-angle glaucoma	DISSZEE8	Strong	Genetic Variation	[10]
Polycystic kidney disease	DISWS3UY	Strong	Biomarker	[1]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[1]
Major depressive disorder	DIS4CL3X	moderate	Altered Expression	[8]
Bipolar depression	DISA75FU	Limited	Altered Expression	[8]
Bipolar disorder	DISAM7J2	Limited	Biomarker	[8]
Myopia	DISK5S60	Limited	Genetic Variation	[11]
Renal dysplasia, cystic, susceptibility to	DIS5AA1I	Limited	Autosomal dominant	[12]

2 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 Protein bicaudal C homolog 1 (BICC1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein bicaudal C homolog 1 (BICC1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein bicaudal C homolog 1 (BICC1).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein bicaudal C homolog 1 (BICC1).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein bicaudal C homolog 1 (BICC1).	[16]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Protein bicaudal C homolog 1 (BICC1).	[17]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Protein bicaudal C homolog 1 (BICC1).	[18]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Protein bicaudal C homolog 1 (BICC1).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protein bicaudal C homolog 1 (BICC1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein bicaudal C homolog 1 (BICC1).	[22]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone decreases the expression of Protein bicaudal C homolog 1 (BICC1).	[23]

References

• [1] Two mutations in human BICC1 resulting in Wnt pathway hyperactivity associated with cystic renal dysplasia.Hum Mutat. 2012 Jan;33(1):86-90. doi: 10.1002/humu.21610. Epub 2011 Oct 31.
• [2] Evidence that two phenotypically distinct mouse PKD mutations, bpk and jcpk, are allelic.Kidney Int. 1996 Oct;50(4):1158-65. doi: 10.1038/ki.1996.423.
• [3] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [4] Crystal Structure of Bicc1 SAM Polymer and Mapping of Interactions between the Ciliopathy-Associated Proteins Bicc1, ANKS3, and ANKS6.Structure. 2018 Feb 6;26(2):209-224.e6. doi: 10.1016/j.str.2017.12.002. Epub 2017 Dec 28.
• [5] Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk.Gastroenterology. 2016 Jun;150(7):1633-1645. doi: 10.1053/j.gastro.2016.02.076. Epub 2016 Mar 8.
• [6] Underlying mechanisms of recombinant adeno-associated virus-mediated bicaudal C homolog 1 overexpression in the medial prefrontal cortex of mice with induced depressive-like behaviors.Brain Res Bull. 2019 Aug;150:35-41. doi: 10.1016/j.brainresbull.2019.05.008. Epub 2019 May 16.
• [7] Genome-wide association study of intraocular pressure uncovers new pathways to glaucoma.Nat Genet. 2018 Aug;50(8):1067-1071. doi: 10.1038/s41588-018-0176-y. Epub 2018 Jul 27.
• [8] Serum BICC1 levels are significantly different in various mood disorders.Neuropsychiatr Dis Treat. 2019 Jan 15;15:259-265. doi: 10.2147/NDT.S190048. eCollection 2019.
• [9] Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.Clin Pharmacol Ther. 2018 Apr;103(4):712-721. doi: 10.1002/cpt.798. Epub 2017 Nov 3.
• [10] A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci.Nat Commun. 2018 Jun 11;9(1):2278. doi: 10.1038/s41467-018-04555-4.
• [11] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [12] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [19] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [20] 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.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [23] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.