Details of Drug Off-Target (DOT)

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

• DOT Name: Cullin-9 (CUL9)
• Synonyms: CUL-9; UbcH7-associated protein 1; p53-associated parkin-like cytoplasmic protein
• Gene Name: CUL9
• Related Disease:
  Precocious puberty
  Beta thalassemia
  Beta-thalassemia major
  Breast cancer
  Breast carcinoma
  Endophthalmitis
  Hypersensitivity pneumonitis
  Idiopathic thrombocytopenic purpura
  Myocardial infarction
  Neoplasm
  Pulmonary sarcoidosis
  Sarcoidosis
  Sjogren syndrome
  Urethritis
  Urinary tract infection
  Chronic obstructive pulmonary disease
  Neuroblastoma
  Niemann-Pick disease type C
  Vascular disease
  Gonococcal urethritis
  Lysosomal acid lipase deficiency
  Nervous system inflammation
  Parkinson disease
  Wolman disease
• UniProt ID: CUL9_HUMAN
• PDB ID: 2JUF
• Pfam ID: PF03256 ; PF11515 ; PF00888 ; PF01485
• Sequence:
  MVGERHAGDLMVPLGPRLQAYPEELIRQRPGHDGHPEYLIRWSVLKCGEVGKVGVEEGKA
  EHILMWLSAPEVYANCPGLLGERALSKGLQHEPAGVSGSFPRDPGGLDEVAMGEMEADVQ
  ALVRRAARQLAESGTPSLTAAVLHTIHVLSAYASIGPLTGVFRETGALDLLMHMLCNPEP
  QIRRSAGKMLQALAAHDAGSRAHVLLSLSQQDGIEQHMDFDSRYTLLELFAETTSSEEHC
  MAFEGIHLPQIPGKLLFSLVKRYLCVTSLLDQLNSSPELGAGDQSSPCATREKSRGQREL
  EFSMAVGNLISELVRSMGWARNLSEQGMSPPRPTRSIFQPYISGPSLLLPTIVTTPRRQG
  WVFRQRSEFSSRSGYGEYVQQTLQPGMRVRMLDDYEEISAGDEGEFRQSNNGIPPVQVFW
  QSTGRTYWVHWHMLEILGPEEATEDKASAAVEKGAGATVLGTAFPSWDWNPMDGLYPLPY
  LQPEPQKNERVGYLTQAEWWELLFFIKKLDLCEQQPIFQNLWKNLDETLGEKALGEISVS
  VEMAESLLQVLSSRFEGSTLNDLLNSQIYTKYGLLSNEPSSSSTSRNHSCTPDPEEESKS
  EASFSEEETESLKAKAEAPKTEAEPTKTRTETPMAQSDSQLFNQLLVTEGMTLPTEMKEA
  ASEMARALRGPGPRSSLDQHVAAVVATVQISSLDTNLQLSGLSALSQAVEEVTERDHPLV
  RPDRSLREKLVKMLVELLTNQVGEKMVVVQALRLLYLLMTKHEWRPLFAREGGIYAVLVC
  MQEYKTSVLVQQAGLAALKMLAVASSSEIPTFVTGRDSIHSLFDAQMTREIFASIDSATR
  PGSESLLLTVPAAVILMLNTEGCSSAARNGLLLLNLLLCNHHTLGDQIITQELRDTLFRH
  SGIAPRTEPMPTTRTILMMLLNRYSEPPGSPERAALETPIIQGQDGSPELLIRSLVGGPS
  AELLLDLERVLCREGSPGGAVRPLLKRLQQETQPFLLLLRTLDAPGPNKTLLLSVLRVIT
  RLLDFPEAMVLPWHEVLEPCLNCLSGPSSDSEIVQELTCFLHRLASMHKDYAVVLCCLGA
  KEILSKVLDKHSAQLLLGCELRDLVTECEKYAQLYSNLTSSILAGCIQMVLGQIEDHRRT
  HQPINIPFFDVFLRHLCQGSSVEVKEDKCWEKVEVSSNPHRASKLTDHNPKTYWESNGST
  GSHYITLHMHRGVLVRQLTLLVASEDSSYMPARVVVFGGDSTSCIGTELNTVNVMPSASR
  VILLENLNRFWPIIQIRIKRCQQGGIDTRVRGVEVLGPKPTFWPLFREQLCRRTCLFYTI
  RAQAWSRDIAEDHRRLLQLCPRLNRVLRHEQNFADRFLPDDEAAQALGKTCWEALVSPLV
  QNITSPDAEGVSALGWLLDQYLEQRETSRNPLSRAASFASRVRRLCHLLVHVEPPPGPSP
  EPSTRPFSKNSKGRDRSPAPSPVLPSSSLRNITQCWLSVVQEQVSRFLAAAWRAPDFVPR
  YCKLYEHLQRAGSELFGPRAAFMLALRSGFSGALLQQSFLTAAHMSEQFARYIDQQIQGG
  LIGGAPGVEMLGQLQRHLEPIMVLSGLELATTFEHFYQHYMADRLLSFGSSWLEGAVLEQ
  IGLCFPNRLPQLMLQSLSTSEELQRQFHLFQLQRLDKLFLEQEDEEEKRLEEEEEEEEEE
  EAEKELFIEDPSPAISILVLSPRCWPVSPLCYLYHPRKCLPTEFCDALDRFSSFYSQSQN
  HPVLDMGPHRRLQWTWLGRAELQFGKQILHVSTVQMWLLLKFNQTEEVSVETLLKDSDLS
  PELLLQALVPLTSGNGPLTLHEGQDFPHGGVLRLHEPGPQRSGEALWLIPPQAYLNVEKD
  EGRTLEQKRNLLSCLLVRILKAHGEKGLHIDQLVCLVLEAWQKGPNPPGTLGHTVAGGVA
  CTSTDVLSCILHLLGQGYVKRRDDRPQILMYAAPEPMGPCRGQADVPFCGSQSETSKPSP
  EAVATLASLQLPAGRTMSPQEVEGLMKQTVRQVQETLNLEPDVAQHLLAHSHWGAEQLLQ
  SYSEDPEPLLLAAGLCVHQAQAVPVRPDHCPVCVSPLGCDDDLPSLCCMHYCCKSCWNEY
  LTTRIEQNLVLNCTCPIADCPAQPTGAFIRAIVSSPEVISKYEKALLRGYVESCSNLTWC
  TNPQGCDRILCRQGLGCGTTCSKCGWASCFNCSFPEAHYPASCGHMSQWVDDGGYYDGMS
  VEAQSKHLAKLISKRCPSCQAPIEKNEGCLHMTCAKCNHGFCWRCLKSWKPNHKDYYNCS
  AMVSKAARQEKRFQDYNERCTFHHQAREFAVNLRNRVSAIHEVPPPRSFTFLNDACQGLE
  QARKVLAYACVYSFYSQDAEYMDVVEQQTENLELHTNALQILLEETLLRCRDLASSLRLL
  RADCLSTGMELLRRIQERLLAILQHSAQDFRVGLQSPSVEAWEAKGPNMPGSQPQASSGP
  EAEEEEEDDEDDVPEWQQDEFDEELDNDSFSYDESENLDQETFFFGDEEEDEDEAYD
• Function: Core component of a Cul9-RING ubiquitin-protein ligase complex, a complex that mediates ubiquitination and subsequent degradation of BIRC5 and is required to maintain microtubule dynamics and genome integrity. Acts downstream of the 3M complex, which inhibits CUL9 activity, leading to prevent ubiquitination of BIRC5. Cytoplasmic anchor protein in p53/TP53-associated protein complex. Regulates the subcellular localization of p53/TP53 and subsequent function.
• Tissue Specificity: Ubiquitously expressed in all tissues with highest expression in testis brain and kidney.
• Reactome Pathway: Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Precocious puberty	DISYI2XZ	Definitive	Biomarker	[1]
Beta thalassemia	DIS5RCQK	Strong	Biomarker	[2]
Beta-thalassemia major	DISW06BV	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Endophthalmitis	DISCQV4J	Strong	Genetic Variation	[4]
Hypersensitivity pneumonitis	DIS5IW5K	Strong	Altered Expression	[5]
Idiopathic thrombocytopenic purpura	DISFKGJU	Strong	Biomarker	[6]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Pulmonary sarcoidosis	DIS1XQCN	Strong	Altered Expression	[9]
Sarcoidosis	DISE5B8Z	Strong	Altered Expression	[9]
Sjogren syndrome	DISUBX7H	Strong	Altered Expression	[10]
Urethritis	DISSWPSQ	Strong	Genetic Variation	[11]
Urinary tract infection	DISMT6UV	Strong	Genetic Variation	[12]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Altered Expression	[13]
Neuroblastoma	DISVZBI4	moderate	Altered Expression	[14]
Niemann-Pick disease type C	DIS492ZO	moderate	Biomarker	[15]
Vascular disease	DISVS67S	moderate	Altered Expression	[13]
Gonococcal urethritis	DISH6EOW	Limited	Genetic Variation	[16]
Lysosomal acid lipase deficiency	DISO6W4Z	Limited	Biomarker	[17]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[18]
Parkinson disease	DISQVHKL	Limited	Biomarker	[19]
Wolman disease	DIS8BKL5	Limited	Biomarker	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cullin-9 (CUL9).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Cullin-9 (CUL9).	[21]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Cullin-9 (CUL9).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Cullin-9 (CUL9).	[23]

References

• [1] Effect of cyproterone acetate on active and inactive renin secretion in patients with precocious puberty and genetic short stature.Horm Res. 1991;36(5-6):216-9. doi: 10.1159/000182166.
• [2] Elevated plasma chemokine CCL18/PARC in beta-thalassemia.Blood Cells Mol Dis. 2005 Nov-Dec;35(3):328-31. doi: 10.1016/j.bcmd.2005.07.006. Epub 2005 Aug 31.
• [3] Association of mRNA expression levels of Cullin family members with prognosis in breast cancer: An online database analysis.Medicine (Baltimore). 2019 Aug;98(31):e16625. doi: 10.1097/MD.0000000000016625.
• [4] Gatifloxacin, moxifloxacin, and balofloxacin resistance due to mutations in the gyrA and parC genes of Staphylococcus epidermidis strains isolated from patients with endophthalmitis, corneal ulcers and conjunctivitis.Ophthalmic Res. 2009;42(1):43-8. doi: 10.1159/000219684. Epub 2009 May 28.
• [5] CCL18/DC-CK-1/PARC up-regulation in hypersensitivity pneumonitis.J Leukoc Biol. 2001 Oct;70(4):610-6.
• [6] Idiopathic thrombocytopenic purpura (ITP): is there a genetic predisposition?.Pediatr Blood Cancer. 2006 Oct 15;47(5 Suppl):678-80. doi: 10.1002/pbc.21005.
• [7] Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations.Atherosclerosis. 2011 Mar;215(1):145-52. doi: 10.1016/j.atherosclerosis.2010.12.005. Epub 2010 Dec 15.
• [8] Cytoplasmic E3 ubiquitin ligase CUL9 controls cell proliferation, senescence, apoptosis and genome integrity through p53.Oncogene. 2017 Sep 7;36(36):5212-5218. doi: 10.1038/onc.2017.141. Epub 2017 May 8.
• [9] Expression of the chemokine PARC mRNA in bronchoalveolar cells of patients with sarcoidosis.Immunol Lett. 2002 Oct 21;84(1):17-22. doi: 10.1016/s0165-2478(02)00130-x.
• [10] "Lymphoid" chemokine messenger RNA expression by epithelial cells in the chronic inflammatory lesion of the salivary glands of Sjgren's syndrome patients: possible participation in lymphoid structure formation.Arthritis Rheum. 2001 Feb;44(2):408-18. doi: 10.1002/1529-0131(200102)44:2<408::AID-ANR60>3.0.CO;2-0.
• [11] Macrolide and fluoroquinolone resistance is uncommon in clinical strains of Chlamydia trachomatis.J Infect Chemother. 2018 Aug;24(8):610-614. doi: 10.1016/j.jiac.2018.03.007. Epub 2018 Apr 4.
• [12] High frequency of aac(6')-Ib-cr gene associated with double mutations in gyrA and parC in Escherichia coli isolates from patients with urinary tract infections.J Glob Antimicrob Resist. 2018 Jun;13:180-183. doi: 10.1016/j.jgar.2017.12.013. Epub 2018 Jan 4.
• [13] Vascular disease in COPD: Systemic and pulmonary expression of PARC (Pulmonary and Activation-Regulated Chemokine).PLoS One. 2017 May 18;12(5):e0177218. doi: 10.1371/journal.pone.0177218. eCollection 2017.
• [14] The Ews/Fli-1 fusion gene changes the status of p53 in neuroblastoma tumor cell lines.Cancer Res. 2004 Oct 15;64(20):7288-95. doi: 10.1158/0008-5472.CAN-04-1610.
• [15] Assessment of plasma chitotriosidase activity, CCL18/PARC concentration and NP-C suspicion index in the diagnosis of Niemann-Pick disease type C: a prospective observational study.J Transl Med. 2017 Feb 21;15(1):43. doi: 10.1186/s12967-017-1146-3.
• [16] Mutations in the gyrA and parC genes and in vitro activities of fluoroquinolones in 91 clinical isolates of Neisseria gonorrhoeae in Japan.Sex Transm Dis. 2004 Mar;31(3):180-4. doi: 10.1097/01.olq.0000114654.91972.66.
• [17] Evaluation of two approaches to lysosomal acid lipase deficiency patient identification: An observational retrospective study.Atherosclerosis. 2019 Jun;285:49-54. doi: 10.1016/j.atherosclerosis.2019.03.013. Epub 2019 Mar 18.
• [18] Novel genes in brain tissues of EAE-induced normal and obese mice: Upregulation of metal ion-binding protein genes in obese-EAE mice.Neuroscience. 2017 Feb 20;343:322-336. doi: 10.1016/j.neuroscience.2016.12.002. Epub 2016 Dec 10.
• [19] Identification of far upstream element-binding protein-1 as an authentic Parkin substrate.J Biol Chem. 2006 Jun 16;281(24):16193-6. doi: 10.1074/jbc.C600041200. Epub 2006 May 3.
• [20] 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.
• [21] 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.
• [22] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.