Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFFKG79)

• DOT Name: BRCA2 and CDKN1A-interacting protein (BCCIP)
• Synonyms: P21- and CDK-associated protein 1; Protein TOK-1
• Gene Name: BCCIP
• Related Disease:
  Advanced cancer
  Astrocytoma
  Brain cancer
  Brain neoplasm
  Breast neoplasm
  Esophageal squamous cell carcinoma
  Glioblastoma multiforme
  Hepatitis C virus infection
  Hereditary breast ovarian cancer syndrome
  Kidney neoplasm
  Neoplasm
  Triple negative breast cancer
  Colorectal carcinoma
  Breast cancer
  Breast carcinoma
  Epithelial ovarian cancer
  Mucinous adenocarcinoma
  Ovarian cancer
  Ovarian neoplasm
• UniProt ID: BCCIP_HUMAN
• PDB ID: 7KYQ; 7KYS; 8EQB; 8EXE; 8EXF
• Pfam ID: PF13862
• Sequence:
  MASRSKRRAVESGVPQPPDPPVQRDEEEEKEVENEDEDDDDSDKEKDEEDEVIDEEVNIE
  FEAYSLSDNDYDGIKKLLQQLFLKAPVNTAELTDLLIQQNHIGSVIKQTDVSEDSNDDMD
  EDEVFGFISLLNLTERKGTQCVEQIQELVLRFCEKNCEKSMVEQLDKFLNDTTKPVGLLL
  SERFINVPPQIALPMYQQLQKELAGAHRTNKPCGKCYFYLLISKTFVEAGKNNSKKKPSN
  KKKAALMFANAEEEFFYEKAILKFNYSVQEESDTCLGGKWSFDDVPMTPLRTVMLIPGDK
  MNEIMDKLKEYLSV
• Function: During interphase, required for microtubule organizing and anchoring activities. During mitosis, required for the organization and stabilization of the spindle pole. Isoform 2/alpha is particularly important for the regulation of microtubule anchoring, microtubule stability, spindle architecture and spindle orientation, compared to isoform 1/beta. May promote cell cycle arrest by enhancing the inhibition of CDK2 activity by CDKN1A. May be required for repair of DNA damage by homologous recombination in conjunction with BRCA2. May not be involved in non-homologous end joining (NHEJ).
• Tissue Specificity: Expressed at high levels in testis and skeletal muscle and at lower levels in brain, heart, kidney, liver, lung, ovary, pancreas, placenta, and spleen.

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Astrocytoma	DISL3V18	Strong	Biomarker	[2]
Brain cancer	DISBKFB7	Strong	Biomarker	[3]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[5]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[6]
Hereditary breast ovarian cancer syndrome	DISWDUGU	Strong	Genetic Variation	[1]
Kidney neoplasm	DISBNZTN	Strong	Altered Expression	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Triple negative breast cancer	DISAMG6N	Strong	Genetic Variation	[8]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[9]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[8]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[8]
Epithelial ovarian cancer	DIS56MH2	Limited	Altered Expression	[10]
Mucinous adenocarcinoma	DISKNFE8	Limited	Altered Expression	[10]
Ovarian cancer	DISZJHAP	Limited	Altered Expression	[10]
Ovarian neoplasm	DISEAFTY	Limited	Altered Expression	[10]

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 BRCA2 and CDKN1A-interacting protein (BCCIP).	[11]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of BRCA2 and CDKN1A-interacting protein (BCCIP).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of BRCA2 and CDKN1A-interacting protein (BCCIP).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of BRCA2 and CDKN1A-interacting protein (BCCIP).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of BRCA2 and CDKN1A-interacting protein (BCCIP).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of BRCA2 and CDKN1A-interacting protein (BCCIP).	[15]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of BRCA2 and CDKN1A-interacting protein (BCCIP).	[16]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of BRCA2 and CDKN1A-interacting protein (BCCIP).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of BRCA2 and CDKN1A-interacting protein (BCCIP).	[18]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of BRCA2 and CDKN1A-interacting protein (BCCIP).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of BRCA2 and CDKN1A-interacting protein (BCCIP).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of BRCA2 and CDKN1A-interacting protein (BCCIP).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of BRCA2 and CDKN1A-interacting protein (BCCIP).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of BRCA2 and CDKN1A-interacting protein (BCCIP).	[24]

References

• [1] Mutation analysis of the BCCIP gene for breast cancer susceptibility in breast/ovarian cancer families.Gynecol Oncol. 2013 Nov;131(2):460-3. doi: 10.1016/j.ygyno.2013.07.104. Epub 2013 Jul 31.
• [2] Alterations of BCCIP, a BRCA2 interacting protein, in astrocytomas.BMC Cancer. 2009 Aug 4;9:268. doi: 10.1186/1471-2407-9-268.
• [3] Inhibition of breast and brain cancer cell growth by BCCIPalpha, an evolutionarily conserved nuclear protein that interacts with BRCA2.Oncogene. 2001 Jan 18;20(3):336-45. doi: 10.1038/sj.onc.1204098.
• [4] BRCA2 gene mutations in Greek patients with familial breast cancer.Hum Mutat. 2002 Jan;19(1):81-2. doi: 10.1002/humu.9003.
• [5] High Expression of BCCIP Can Promote Proliferation of Esophageal Squamous Cell Carcinoma.Dig Dis Sci. 2017 Feb;62(2):387-395. doi: 10.1007/s10620-016-4382-0. Epub 2016 Dec 19.
• [6] FUSE Binding Protein 1 Facilitates Persistent Hepatitis C Virus Replication in Hepatoma Cells by Regulating Tumor Suppressor p53.J Virol. 2015 Aug;89(15):7905-21. doi: 10.1128/JVI.00729-15. Epub 2015 May 20.
• [7] Genomic structure of the human BCCIP gene and its expression in cancer.Gene. 2003 Jan 2;302(1-2):139-46. doi: 10.1016/s0378-1119(02)01098-3.
• [8] Roles of BCCIP deficiency in mammary tumorigenesis.Breast Cancer Res. 2017 Oct 18;19(1):115. doi: 10.1186/s13058-017-0907-5.
• [9] Celecoxib enhances the radiosensitivity of HCT116 cells in a COX-2 independent manner by up-regulating BCCIP.Am J Transl Res. 2017 Mar 15;9(3):1088-1100. eCollection 2017.
• [10] Differential BCCIP gene expression in primary human ovarian cancer, renal cell carcinoma and colorectal cancer tissues.Int J Oncol. 2013 Dec;43(6):1925-34. doi: 10.3892/ijo.2013.2124. Epub 2013 Oct 3.
• [11] 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.
• [12] Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [15] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [16] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [17] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [20] Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP. Toxicology. 2021 Jan 30;448:152652. doi: 10.1016/j.tox.2020.152652. Epub 2020 Dec 2.
• [21] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.