Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXPE1UZ)

DOT Name	Cullin-1 (CUL1)
Synonyms	CUL-1
Gene Name	CUL1
Related Disease	Nervous system disease ( ) Parkinson disease ( ) Adult glioblastoma ( ) Benign neoplasm ( ) Breast cancer ( ) Breast carcinoma ( ) Clear cell renal carcinoma ( ) Colon cancer ( ) Colon carcinoma ( ) Glioblastoma multiforme ( ) Glioma ( ) Hepatocellular carcinoma ( ) Kidney cancer ( ) Malignant mesothelioma ( ) Malignant peripheral nerve sheath tumor ( ) Renal carcinoma ( ) Renal cell carcinoma ( ) Rheumatoid arthritis ( ) Stevens-Johnson syndrome ( ) T-cell lymphoma ( ) Toxic epidermal necrolysis ( ) Transitional cell carcinoma ( ) Triple negative breast cancer ( ) Urothelial carcinoma ( ) Advanced cancer ( ) Choriocarcinoma ( ) Bone osteosarcoma ( ) Crohn disease ( ) Huntington disease ( ) Inflammatory bowel disease ( ) Malignant pleural mesothelioma ( ) Melanoma ( ) Neoplasm ( ) Neuroblastoma ( ) Osteosarcoma ( ) Spinocerebellar ataxia type 3 ( ) Squamous cell carcinoma ( ) Type-1/2 diabetes ( )
UniProt ID	CUL1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	1LDJ; 1LDK; 1U6G; 3RTR; 3TDU; 3TDZ; 4F52; 4P5O; 5V89; 6TTU; 6WCQ; 7B5L; 7B5M; 7B5N; 7B5R; 7B5S; 7Z8R; 7Z8T; 7Z8V; 7ZBW; 7ZBZ; 8CAF; 8CDJ; 8CDK; 8OR0; 8OR2; 8OR3; 8OR4
Pfam ID	PF00888 ; PF10557
Sequence	MSSTRSQNPHGLKQIGLDQIWDDLRAGIQQVYTRQSMAKSRYMELYTHVYNYCTSVHQSN QARGAGVPPSKSKKGQTPGGAQFVGLELYKRLKEFLKNYLTNLLKDGEDLMDESVLKFYT QQWEDYRFSSKVLNGICAYLNRHWVRRECDEGRKGIYEIYSLALVTWRDCLFRPLNKQVT NAVLKLIEKERNGETINTRLISGVVQSYVELGLNEDDAFAKGPTLTVYKESFESQFLADT ERFYTRESTEFLQQNPVTEYMKKAEARLLEEQRRVQVYLHESTQDELARKCEQVLIEKHL EIFHTEFQNLLDADKNEDLGRMYNLVSRIQDGLGELKKLLETHIHNQGLAAIEKCGEAAL NDPKMYVQTVLDVHKKYNALVMSAFNNDAGFVAALDKACGRFINNNAVTKMAQSSSKSPE LLARYCDSLLKKSSKNPEEAELEDTLNQVMVVFKYIEDKDVFQKFYAKMLAKRLVHQNSA SDDAEASMISKLKQACGFEYTSKLQRMFQDIGVSKDLNEQFKKHLTNSEPLDLDFSIQVL SSGSWPFQQSCTFALPSELERSYQRFTAFYASRHSGRKLTWLYQLSKGELVTNCFKNRYT LQASTFQMAILLQYNTEDAYTVQQLTDSTQIKMDILAQVLQILLKSKLLVLEDENANVDE VELKPDTLIKLYLGYKNKKLRVNINVPMKTEQKQEQETTHKNIEEDRKLLIQAAIVRIMK MRKVLKHQQLLGEVLTQLSSRFKPRVPVIKKCIDILIEKEYLERVDGEKDTYSYLA
Function	Core component of multiple cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. SCF complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins. In the SCF complex, serves as a rigid scaffold that organizes the SKP1-F-box protein and RBX1 subunits. May contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and exchange of the substrate recognition component is mediated by TIP120A/CAND1. The functional specificity of the SCF complex depends on the F-box protein as substrate recognition component. SCF(BTRC) and SCF(FBXW11) direct ubiquitination of CTNNB1 and participate in Wnt signaling. SCF(FBXW11) directs ubiquitination of phosphorylated NFKBIA. SCF(BTRC) directs ubiquitination of NFKBIB, NFKBIE, ATF4, SMAD3, SMAD4, CDC25A, FBXO5 and probably NFKB2. SCF(BTRC) and/or SCF(FBXW11) direct ubiquitination of CEP68. SCF(SKP2) directs ubiquitination of phosphorylated CDKN1B/p27kip and is involved in regulation of G1/S transition. SCF(SKP2) directs ubiquitination of ORC1, CDT1, RBL2, ELF4, CDKN1A, RAG2, FOXO1A, and probably MYC and TAL1. SCF(FBXW7) directs ubiquitination of CCNE1, NOTCH1 released notch intracellular domain (NICD), and probably PSEN1. SCF(FBXW2) directs ubiquitination of GCM1. SCF(FBXO32) directs ubiquitination of MYOD1. SCF(FBXO7) directs ubiquitination of BIRC2 and DLGAP5. SCF(FBXO33) directs ubiquitination of YBX1. SCF(FBXO1) directs ubiquitination of BCL6 and DTL but does not seem to direct ubiquitination of TP53. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(CCNF) directs ubiquitination of CCP110. SCF(FBXL3) and SCF(FBXL21) direct ubiquitination of CRY1 and CRY2. SCF(FBXO9) directs ubiquitination of TTI1 and TELO2. SCF(FBXO10) directs ubiquitination of BCL2.
Tissue Specificity	Expressed in lung fibroblasts.
KEGG Pathway	Cell cycle (hsa04110 ) Oocyte meiosis (hsa04114 ) Ubiquitin mediated proteolysis (hsa04120 ) Protein processing in endoplasmic reticulum (hsa04141 ) Wnt sig.ling pathway (hsa04310 ) Hedgehog sig.ling pathway (hsa04340 ) TGF-beta sig.ling pathway (hsa04350 ) Circadian rhythm (hsa04710 ) Shigellosis (hsa05131 ) Human immunodeficiency virus 1 infection (hsa05170 ) Pathways in cancer (hsa05200 )
Reactome Pathway	Prolactin receptor signaling (R-HSA-1170546 ) SCF-beta-TrCP mediated degradation of Emi1 (R-HSA-174113 ) SCF(Skp2)-mediated degradation of p27/p21 (R-HSA-187577 ) Degradation of beta-catenin by the destruction complex (R-HSA-195253 ) Downstream TCR signaling (R-HSA-202424 ) NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947 ) Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942 ) Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606 ) Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling (R-HSA-2644607 ) FCERI mediated NF-kB activation (R-HSA-2871837 ) Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862 ) Circadian Clock (R-HSA-400253 ) Dectin-1 mediated noncanonical NF-kB signaling (R-HSA-5607761 ) CLEC7A (Dectin-1) signaling (R-HSA-5607764 ) Degradation of GLI1 by the proteasome (R-HSA-5610780 ) Degradation of GLI2 by the proteasome (R-HSA-5610783 ) GLI3 is processed to GLI3R by the proteasome (R-HSA-5610785 ) NIK-->noncanonical NF-kB signaling (R-HSA-5676590 ) MAP3K8 (TPL2)-dependent MAPK1/3 activation (R-HSA-5684264 ) Orc1 removal from chromatin (R-HSA-68949 ) Cyclin D associated events in G1 (R-HSA-69231 ) FBXL7 down-regulates AURKA during mitotic entry and in early mitosis (R-HSA-8854050 ) Regulation of RUNX2 expression and activity (R-HSA-8939902 ) Neddylation (R-HSA-8951664 ) Interleukin-1 signaling (R-HSA-9020702 ) Iron uptake and transport (R-HSA-917937 ) Negative regulation of NOTCH4 signaling (R-HSA-9604323 ) Regulation of BACH1 activity (R-HSA-9708530 ) Nuclear events stimulated by ALK signaling in cancer (R-HSA-9725371 ) GSK3B and BTRC (R-HSA-9762114 ) Antigen processing (R-HSA-983168 ) Activation of NF-kappaB in B cells (R-HSA-1169091 )
BioCyc Pathway	MetaCyc:ENSG00000055130-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

38 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Nervous system disease	DISJ7GGT	Definitive	Biomarker	[1]
Parkinson disease	DISQVHKL	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Benign neoplasm	DISDUXAD	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Glioma	DIS5RPEH	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Kidney cancer	DISBIPKM	Strong	Biomarker	[7]
Malignant mesothelioma	DISTHJGH	Strong	Biomarker	[8]
Malignant peripheral nerve sheath tumor	DIS0JTN6	Strong	Genetic Variation	[9]
Renal carcinoma	DISER9XT	Strong	Altered Expression	[4]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[4]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[10]
Stevens-Johnson syndrome	DISZG4YX	Strong	Biomarker	[11]
T-cell lymphoma	DISSXRTQ	Strong	Biomarker	[12]
Toxic epidermal necrolysis	DISIWPFR	Strong	Biomarker	[11]
Transitional cell carcinoma	DISWVVDR	Strong	Altered Expression	[13]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[3]
Urothelial carcinoma	DISRTNTN	Strong	Altered Expression	[13]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[14]
Choriocarcinoma	DISDBVNL	moderate	Altered Expression	[15]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[16]
Crohn disease	DIS2C5Q8	Limited	Genetic Variation	[17]
Huntington disease	DISQPLA4	Limited	Altered Expression	[18]
Inflammatory bowel disease	DISGN23E	Limited	Genetic Variation	[17]
Malignant pleural mesothelioma	DIST2R60	Limited	Biomarker	[19]
Melanoma	DIS1RRCY	Limited	Biomarker	[20]
Neoplasm	DISZKGEW	Limited	Biomarker	[3]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[21]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[16]
Spinocerebellar ataxia type 3	DISQBQID	Limited	Altered Expression	[22]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[23]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[24]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

3 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 Cullin-1 (CUL1).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Cullin-1 (CUL1).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Cullin-1 (CUL1).	[35]
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11 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cullin-1 (CUL1).	[26]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cullin-1 (CUL1).	[27]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cullin-1 (CUL1).	[28]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cullin-1 (CUL1).	[29]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Cullin-1 (CUL1).	[30]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Cullin-1 (CUL1).	[31]
Sertraline	DM0FB1J	Approved	Sertraline decreases the expression of Cullin-1 (CUL1).	[32]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Cullin-1 (CUL1).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Cullin-1 (CUL1).	[36]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Cullin-1 (CUL1).	[37]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Cullin-1 (CUL1).	[38]
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⏷ Show the Full List of 11 Drug(s)

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Cullin-1 (CUL1).	[33]
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References

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2	Cullin1 regulates proliferation, migration and invasion of glioma cells.Med Oncol. 2014 Oct;31(10):227. doi: 10.1007/s12032-014-0227-x. Epub 2014 Sep 9.
3	CUL1 Knockdown Attenuates the Adhesion, Invasion, and Migration of Triple-Negative Breast Cancer Cells via Inhibition of Epithelial-Mesenchymal Transition.Pathol Oncol Res. 2020 Apr;26(2):1153-1163. doi: 10.1007/s12253-019-00681-6. Epub 2019 Jun 7.
4	The expression of Cullin1 is increased in renal cell carcinoma and promotes cancer cell proliferation, migration, and invasion.Tumour Biol. 2016 Sep;37(9):12823-12831. doi: 10.1007/s13277-016-5151-6. Epub 2016 Jul 23.
5	The Nedd8-activating enzyme inhibitor MLN4924 suppresses colon cancer cell growth via triggering autophagy.Korean J Physiol Pharmacol. 2018 Nov;22(6):617-625. doi: 10.4196/kjpp.2018.22.6.617. Epub 2018 Oct 25.
6	Molecular targeting of CSN5 in human hepatocellular carcinoma: a mechanism of therapeutic response.Oncogene. 2011 Oct 6;30(40):4175-84. doi: 10.1038/onc.2011.126. Epub 2011 Apr 18.
7	Expression and clinical significance of CacyBP/SIP in pancreatic cancer.Pancreatology. 2008;8(4-5):470-7. doi: 10.1159/000151774. Epub 2008 Sep 3.
8	Driver Gene and Novel Mutations in Asbestos-Exposed Lung Adenocarcinoma and Malignant Mesothelioma Detected by Exome Sequencing.Lung. 2016 Feb;194(1):125-35. doi: 10.1007/s00408-015-9814-7.
9	Genome-wide high-resolution analysis of DNA copy number alterations in NF1-associated malignant peripheral nerve sheath tumors using 32K BAC array.Genes Chromosomes Cancer. 2009 Oct;48(10):897-907. doi: 10.1002/gcc.20695.
10	Association of Cullin1 haplotype variants with rheumatoid arthritis and response to methotrexate.Pharmacogenet Genomics. 2011 Sep;21(9):590-3. doi: 10.1097/FPC.0b013e3283492af7.
11	Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
12	In vivo interference with Skp1 function leads to genetic instability and neoplastic transformation.Mol Cell Biol. 2002 Dec;22(23):8375-87. doi: 10.1128/MCB.22.23.8375-8387.2002.
13	Expression of CUL1 correlates with tumour-grade and recurrence in urothelial carcinoma.ANZ J Surg. 2017 Jul;87(7-8):624-629. doi: 10.1111/ans.13438. Epub 2016 Jun 16.
14	Dissecting the function of Cullin-RING ubiquitin ligase complex genes in planarian regeneration.Dev Biol. 2018 Jan 15;433(2):210-217. doi: 10.1016/j.ydbio.2017.10.011. Epub 2017 Dec 25.
15	CUL1 promotes trophoblast cell invasion at the maternal-fetal interface.Cell Death Dis. 2013 Feb 21;4(2):e502. doi: 10.1038/cddis.2013.1.
16	Cullin-1 regulates MG63 cell proliferation and metastasis and is a novel prognostic marker of osteosarcoma.Int J Biol Markers. 2017 May 4;32(2):e202-e209. doi: 10.5301/jbm.5000247.
17	Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
18	Dysregulation of core components of SCF complex in poly-glutamine disorders.Cell Death Dis. 2012 Nov 22;3(11):e428. doi: 10.1038/cddis.2012.166.
19	Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma.Cancer Res. 2015 Jan 15;75(2):264-9. doi: 10.1158/0008-5472.CAN-14-1008. Epub 2014 Dec 8.
20	Cul1 promotes melanoma cell proliferation by promoting DEPTOR degradation and enhancing cap-dependent translation.Oncol Rep. 2016 Feb;35(2):1049-56. doi: 10.3892/or.2015.4442. Epub 2015 Nov 23.
21	Retinoic acid induces REST degradation and neuronal differentiation by modulating the expression of SCF(-TRCP) in neuroblastoma cells.Cancer. 2011 Nov 15;117(22):5189-202. doi: 10.1002/cncr.26145. Epub 2011 Apr 26.
22	FipoQ/FBXO33, a Cullin-1-based ubiquitin ligase complex component modulates ubiquitination and solubility of polyglutamine disease protein.J Neurochem. 2019 Jun;149(6):781-798. doi: 10.1111/jnc.14669. Epub 2019 Feb 28.
23	Piperidinyl Ureas Chemically Control Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation.J Med Chem. 2018 Apr 12;61(7):2680-2693. doi: 10.1021/acs.jmedchem.7b01277. Epub 2018 Mar 26.
24	Cullin-1 promotes cell proliferation in human breast cancer and is related to diabetes.Int J Biol Markers. 2016 Dec 23;31(4):e375-e381. doi: 10.5301/jbm.5000215.
25	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.
26	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.
27	Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
28	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
29	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.
30	A comprehensive analysis of Wnt/beta-catenin signaling pathway-related genes and crosstalk pathways in the treatment of As2O3 in renal cancer. Ren Fail. 2018 Nov;40(1):331-339.
31	Induction of heme oxygenase-1 by cobalt protoporphyrin enhances the antitumour effect of bortezomib in adult T-cell leukaemia cells. Br J Cancer. 2007 Oct 22;97(8):1099-105. doi: 10.1038/sj.bjc.6604003. Epub 2007 Sep 25.
32	Sertraline induces endoplasmic reticulum stress in hepatic cells. Toxicology. 2014 Aug 1;322:78-88. doi: 10.1016/j.tox.2014.05.007. Epub 2014 May 24.
33	Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
34	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.
35	DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
36	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.
37	Integrated analysis of paraquat-induced microRNAs-mRNAs changes in human neural progenitor cells. Toxicol In Vitro. 2017 Oct;44:196-205. doi: 10.1016/j.tiv.2017.06.010. Epub 2017 Jun 12.
38	Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.