Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWRIMZ3)

• DOT Name: Centromere protein I (CENPI)
• Synonyms: CENP-I; FSH primary response protein 1; Follicle-stimulating hormone primary response protein; Interphase centromere complex protein 19; Leucine-rich primary response protein 1
• Gene Name: CENPI
• Related Disease:
  Autoimmune disease
  Breast cancer
  Colorectal carcinoma
  Estrogen-receptor positive breast cancer
  Neoplasm
  Breast carcinoma
  Idiopathic steroid-sensitive nephrotic syndrome
• UniProt ID: CENPI_HUMAN
• PDB ID: 7PB4; 7PKN; 7QOO; 7R5S; 7R5V; 7XHN; 7XHO; 7YWX; 7YYH
• Pfam ID: PF07778
• Sequence:
  MSPQKRVKNVQAQNRTSQGSSSFQTTLSAWKVKQDPSNSKNISKHGQNNPVGDYEHADDQ
  AEEDALQMAVGYFEKGPIKASQNKDKTLEKHLKTVENVAWKNGLASEEIDILLNIALSGK
  FGNAVNTRILKCMIPATVISEDSVVKAVSWLCVGKCSGSTKVLFYRWLVAMFDFIDRKEQ
  INLLYGFFFASLQDDALCPYVCHLLYLLTKKENVKPFRVRKLLDLQAKMGMQPHLQALLS
  LYKFFAPALISVSLPVRKKIYFKNSENLWKTALLAVKQRNRGPSPEPLKLMLGPANVRPL
  KRKWNSLSVIPVLNSSSYTKECGKKEMSLSDCLNRSGSFPLEQLQSFPQLLQNIHCLELP
  SQMGSVLNNSLLLHYINCVRDEPVLLRFYYWLSQTLQEECIWYKVNNYEHGKEFTNFLDT
  IIRAECFLQEGFYSCEAFLYKSLPLWDGLCCRSQFLQLVSWIPFSSFSEVKPLLFDHLAQ
  LFFTSTIYFKCSVLQSLKELLQNWLLWLSMDIHMKPVTNSPLETTLGGSMNSVSKLIHYV
  GWLSTTAMRLESNNTFLLHFILDFYEKVCDIYINYNLPLVVLFPPGIFYSALLSLDTSIL
  NQLCFIMHRYRKNLTAAKKNELVQKTKSEFNFSSKTYQEFNHYLTSMVGCLWTSKPFGKG
  IYIDPEILEKTGVAEYKNSLNVVHHPSFLSYAVSFLLQESPEERTVNVSSIRGKKWSWYL
  DYLFSQGLQGLKLFIRSSVHHSSIPRAEGINCNNQY
• Function: Component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromeres which is involved in assembly of kinetochore proteins, mitotic progression and chromosome segregation. May be involved in incorporation of newly synthesized CENPA into centromeres via its interaction with the CENPA-NAC complex. Required for the localization of CENPF, MAD1L1 and MAD2 (MAD2L1 or MAD2L2) to kinetochores. Involved in the response of gonadal tissues to follicle-stimulating hormone.
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Deposition of new CENPA-containing nucleosomes at the centromere (R-HSA-606279)
  Mitotic Prometaphase (R-HSA-68877)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[2]
Idiopathic steroid-sensitive nephrotic syndrome	DIS8I01R	Limited	X-linked	[4]

25 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 Centromere protein I (CENPI).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Centromere protein I (CENPI).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Centromere protein I (CENPI).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Centromere protein I (CENPI).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Centromere protein I (CENPI).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Centromere protein I (CENPI).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Centromere protein I (CENPI).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Centromere protein I (CENPI).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Centromere protein I (CENPI).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Centromere protein I (CENPI).	[13]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Centromere protein I (CENPI).	[14]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Centromere protein I (CENPI).	[15]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Centromere protein I (CENPI).	[16]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Centromere protein I (CENPI).	[17]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Centromere protein I (CENPI).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Centromere protein I (CENPI).	[19]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of Centromere protein I (CENPI).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Centromere protein I (CENPI).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Centromere protein I (CENPI).	[22]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Centromere protein I (CENPI).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Centromere protein I (CENPI).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Centromere protein I (CENPI).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Centromere protein I (CENPI).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Centromere protein I (CENPI).	[16]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Centromere protein I (CENPI).	[27]

References

• [1] Accounting for eXentricities: analysis of the X chromosome in GWAS reveals X-linked genes implicated in autoimmune diseases.PLoS One. 2014 Dec 5;9(12):e113684. doi: 10.1371/journal.pone.0113684. eCollection 2014.
• [2] CENPI is overexpressed in colorectal cancer and regulates cell migration and invasion.Gene. 2018 Oct 20;674:80-86. doi: 10.1016/j.gene.2018.06.067. Epub 2018 Jun 21.
• [3] Overexpression of the E2F target gene CENPI promotes chromosome instability and predicts poor prognosis in estrogen receptor-positive breast cancer.Oncotarget. 2017 Jul 10;8(37):62167-62182. doi: 10.18632/oncotarget.19131. eCollection 2017 Sep 22.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [14] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [15] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [18] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [21] 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.
• [22] 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.
• [23] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.