Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1O9XYJ)

• DOT Name: Centrosomal protein of 135 kDa (CEP135)
• Synonyms: Cep135; Centrosomal protein 4
• Gene Name: CEP135
• Related Disease:
  Microcephaly 8, primary, autosomal recessive
  Neoplasm
  Seckel syndrome
  Autosomal recessive primary microcephaly
  Breast cancer
  Breast carcinoma
  Proliferative diabetic retinopathy
  Type-1 diabetes
• UniProt ID: CP135_HUMAN
• PDB ID: 5FCN; 5NG4
• Sequence:
  MTTAVERKYINIRKRLDQLGYRQTLTVECLPLVEKLFSDLVHTTESLRQSKLSAVKAEKE
  SANFDFVLEPYKLENARLSRENNELYLELMKLREHSDQHVKELKTSLKKCARETADLKFL
  NNQYAHKLKLLEKESKAKNERIQQLQEKNLHAVVQTPGGKKRSIAFRRQRMQIDEPVPPS
  EVSSYPVPQPDDPYIADLLQVADNRIQELQQEVHQLQEKLAMMESGVRDYSKQIELRERE
  IERLSVALDGGRSPDVLSLESRNKTNEKLIAHLNIQVDFLQQANKDLEKRIRELMETKET
  VTSEVVNLSNKNEKLCQELTEIDQLAQQLERHKEEVLETADKELGEAKKEIKRKLSEMQD
  LEETMAKLQLELNLCQKEKERLSDELLVKSDLETVVHQLEQEKQRLSKKVESFAVTERQL
  TLEVERMRLEHGIKRRDRSPSRLDTFLKGIEEERDYYKKELERLQHIIQRRSCSTSYSAR
  EKSSIFRTPEKGDYNSEIHQITRERDELQRMLERFEKYMEDIQSNVKLLTAERDKLSVLY
  NEAQEELSALRKESTQTTAPHNIVSLMEKEKELALSDLRRIMAEKEALREKLEHIEEVSL
  FGKSELEKTIEHLTCVNHQLESEKYELKSKVLIMKETIESLENKLKVQAQKFSHVAGDSS
  HQKTEVNSLRIVNEQLQRSVDDYQHRLSIKRGELESAQAQIKILEEKIDELNLKMTSQDE
  EAHVMKKTIGVIDKEKDFLQETVDEKTEKIANLQENLANKEKAVAQMKIMISECESSVNQ
  LKETLVNRDREINSLRRQLDAAHKELDEVGRSREIAFKENRRLQDDLATMARENQEISLE
  LEAAVQEKEEMKSRVHKYITEVSRWESLMAAKEKENQDLLDRFQMLHNRAEDWEVKAHQA
  EGESSSVRLELLSIDTERRHLRERVELLEKEIQEHINAHHAYESQISSMAKAMSRLEEEL
  RHQEDEKATVLNDLSSLRELCIKLDSGKDIMTQQLNSKNLEFERVVVELENVKSESDLLK
  KQLSNERHTVKNLESLLATNRDKEFHSHLTSHEKDTEIQLLKEKLTLSESKLTSQSRENT
  MLRAKVAQLQTDYDALKRQISTERYERERAIQEMRRHGLATPPLSSTLRSPSHSPEHRNV
• Function: Centrosomal microtubule-binding protein involved in centriole biogenesis. Acts as a scaffolding protein during early centriole biogenesis. Required for the targeting of centriole satellite proteins to centrosomes such as of PCM1, SSX2IP and CEP290 and recruitment of WRAP73 to centrioles. Also required for centriole-centriole cohesion during interphase by acting as a platform protein for CEP250 at the centriole. Required for the recruitment of CEP295 to the proximal end of new-born centrioles at the centriolar microtubule wall during early S phase in a PLK4-dependent manner.
• Reactome Pathway:
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  AURKA Activation by TPX2 (R-HSA-8854518)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Microcephaly 8, primary, autosomal recessive	DIS4A8DE	Strong	Autosomal recessive	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Seckel syndrome	DISEVUBA	Strong	Biomarker	[3]
Autosomal recessive primary microcephaly	DIS29IE3	Supportive	Autosomal recessive	[4]
Breast cancer	DIS7DPX1	Limited	Biomarker	[5]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[5]
Proliferative diabetic retinopathy	DISQZ13G	Limited	Genetic Variation	[6]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Centrosomal protein of 135 kDa (CEP135).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Centrosomal protein of 135 kDa (CEP135).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Centrosomal protein of 135 kDa (CEP135).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Centrosomal protein of 135 kDa (CEP135).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Centrosomal protein of 135 kDa (CEP135).	[11]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Centrosomal protein of 135 kDa (CEP135).	[12]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Centrosomal protein of 135 kDa (CEP135).	[13]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Centrosomal protein of 135 kDa (CEP135).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Centrosomal protein of 135 kDa (CEP135).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Centrosomal protein of 135 kDa (CEP135).	[16]

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 Centrosomal protein of 135 kDa (CEP135).	[14]

References

• [1] A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function. Am J Hum Genet. 2012 May 4;90(5):871-8. doi: 10.1016/j.ajhg.2012.03.016. Epub 2012 Apr 19.
• [2] Phylogenetic analysis of multiple FISH markers in oral tongue squamous cell carcinoma suggests that a diverse distribution of copy number changes is associated with poor prognosis.Int J Cancer. 2016 Jan 1;138(1):98-109. doi: 10.1002/ijc.29691. Epub 2015 Aug 28.
• [3] Genomic and phenotypic delineation of congenital microcephaly. Genet Med. 2019 Mar;21(3):545-552. doi: 10.1038/s41436-018-0140-3. Epub 2018 Sep 14.
• [4] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [5] CEP135 isoform dysregulation promotes centrosome amplification in breast cancer cells.Mol Biol Cell. 2019 May 1;30(10):1230-1244. doi: 10.1091/mbc.E18-10-0674. Epub 2019 Feb 27.
• [6] The Association of CEP135 rs4865047 and NPY2R rs1902491 Single Nucleotide Polymorphisms (SNPs) with Rapid Progression of Proliferative Diabetic Retinopathy in Patients with Type 1 Diabetes Mellitus.Med Sci Monit. 2018 Dec 8;24:8891-8898. doi: 10.12659/MSM.909803.
• [7] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] 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] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [14] 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.
• [15] 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.
• [16] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.