Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2QX4DO)

• DOT Name: Cullin-4B (CUL4B)
• Synonyms: CUL-4B
• Gene Name: CUL4B
• Related Disease:
  Arthritis
  Neural tube defect
  Type-1 diabetes
  X-linked intellectual disability, Cabezas type
  Advanced cancer
  B-cell lymphoma
  Bladder cancer
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Cerebellar ataxia
  Cholangiocarcinoma
  Colon adenocarcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Congenital contractural arachnodactyly
  Epilepsy
  Esophageal squamous cell carcinoma
  Fanconi anemia complementation group A
  Fanconi's anemia
  Gastric cancer
  Gonorrhea
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Obesity
  Osteosarcoma
  Peripheral neuropathy
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  X-linked intellectual disability
  Carcinoma
  Cervical carcinoma
  Head-neck squamous cell carcinoma
  Non-small-cell lung cancer
  Intellectual disability
  Macular corneal dystrophy
  Movement disorder
  Pancreatic cancer
  Prostate cancer
  Prostate carcinoma
• UniProt ID: CUL4B_HUMAN
• PDB ID: 2DO7; 4A0C; 4A0L; 4A64; 8EI1
• Pfam ID: PF00888 ; PF10557
• Sequence:
  MMSQSSGSGDGNDDEATTSKDGGFSSPSPSAAAAAQEVRSATDGNTSTTPPTSAKKRKLN
  SSSSSSSNSSNEREDFDSTSSSSSTPPLQPRDSASPSTSSFCLGVSVAASSHVPIQKKLR
  FEDTLEFVGFDAKMAEESSSSSSSSSPTAATSQQQQLKNKSILISSVASVHHANGLAKSS
  TTVSSFANSKPGSAKKLVIKNFKDKPKLPENYTDETWQKLKEAVEAIQNSTSIKYNLEEL
  YQAVENLCSYKISANLYKQLRQICEDHIKAQIHQFREDSLDSVLFLKKIDRCWQNHCRQM
  IMIRSIFLFLDRTYVLQNSMLPSIWDMGLELFRAHIISDQKVQNKTIDGILLLIERERNG
  EAIDRSLLRSLLSMLSDLQIYQDSFEQRFLEETNRLYAAEGQKLMQEREVPEYLHHVNKR
  LEEEADRLITYLDQTTQKSLIATVEKQLLGEHLTAILQKGLNNLLDENRIQDLSLLYQLF
  SRVRGGVQVLLQQWIEYIKAFGSTIVINPEKDKTMVQELLDFKDKVDHIIDICFLKNEKF
  INAMKEAFETFINKRPNKPAELIAKYVDSKLRAGNKEATDEELEKMLDKIMIIFRFIYGK
  DVFEAFYKKDLAKRLLVGKSASVDAEKSMLSKLKHECGAAFTSKLEGMFKDMELSKDIMI
  QFKQYMQNQNVPGNIELTVNILTMGYWPTYVPMEVHLPPEMVKLQEIFKTFYLGKHSGRK
  LQWQSTLGHCVLKAEFKEGKKELQVSLFQTLVLLMFNEGEEFSLEEIKQATGIEDGELRR
  TLQSLACGKARVLAKNPKGKDIEDGDKFICNDDFKHKLFRIKINQIQMKETVEEQASTTE
  RVFQDRQYQIDAAIVRIMKMRKTLSHNLLVSEVYNQLKFPVKPADLKKRIESLIDRDYME
  RDKENPNQYNYIA
• Function: Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable substrate recognition subunit. CUL4B may act within the complex as a scaffold protein, contributing to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. Plays a role as part of the E3 ubiquitin-protein ligase complex in polyubiquitination of CDT1, histone H2A, histone H3 and histone H4 in response to radiation-induced DNA damage. Targeted to UV damaged chromatin by DDB2 and may be important for DNA repair and DNA replication. A number of DCX complexes (containing either TRPC4AP or DCAF12 as substrate-recognition component) are part of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation. The DCX(AMBRA1) complex is a master regulator of the transition from G1 to S cell phase by mediating ubiquitination of phosphorylated cyclin-D (CCND1, CCND2 and CCND3). The DCX(AMBRA1) complex also acts as a regulator of Cul5-RING (CRL5) E3 ubiquitin-protein ligase complexes by mediating ubiquitination and degradation of Elongin-C (ELOC) component of CRL5 complexes. Required for ubiquitination of cyclin E (CCNE1 or CCNE2), and consequently, normal G1 cell cycle progression. Regulates the mammalian target-of-rapamycin (mTOR) pathway involved in control of cell growth, size and metabolism. Specific CUL4B regulation of the mTORC1-mediated pathway is dependent upon 26S proteasome function and requires interaction between CUL4B and MLST8. With CUL4A, contributes to ribosome biogenesis.
• KEGG Pathway:
  Nucleotide excision repair (hsa03420)
  Ubiquitin mediated proteolysis (hsa04120)
  Human immunodeficiency virus 1 infection (hsa05170)
• Reactome Pathway:
  DNA Damage Recognition in GG-NER (R-HSA-5696394)
  Formation of Incision Complex in GG-NER (R-HSA-5696395)
  Dual Incision in GG-NER (R-HSA-5696400)
  Formation of TC-NER Pre-Incision Complex (R-HSA-6781823)
  Transcription-Coupled Nucleotide Excision Repair (TC-NER) (R-HSA-6781827)
  Dual incision in TC-NER (R-HSA-6782135)
  Gap-filling DNA repair synthesis and ligation in TC-NER (R-HSA-6782210)
  Neddylation (R-HSA-8951664)
  Recognition of DNA damage by PCNA-containing replication complex (R-HSA-110314)

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthritis	DIST1YEL	Definitive	Biomarker	[1]
Neural tube defect	DIS5J95E	Definitive	Altered Expression	[2]
Type-1 diabetes	DIS7HLUB	Definitive	Biomarker	[3]
X-linked intellectual disability, Cabezas type	DISMADKV	Definitive	X-linked	[4]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[5]
B-cell lymphoma	DISIH1YQ	Strong	Altered Expression	[6]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[7]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[8]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[9]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[9]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[10]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[11]
Colon adenocarcinoma	DISDRE0J	Strong	Biomarker	[5]
Colon cancer	DISVC52G	Strong	Biomarker	[12]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[12]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[13]
Congenital contractural arachnodactyly	DISOM1K7	Strong	Altered Expression	[11]
Epilepsy	DISBB28L	Strong	Biomarker	[14]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[15]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[16]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[16]
Gastric cancer	DISXGOUK	Strong	Biomarker	[17]
Gonorrhea	DISQ5AO6	Strong	Biomarker	[17]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[18]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[19]
Lung cancer	DISCM4YA	Strong	Biomarker	[20]
Lung carcinoma	DISTR26C	Strong	Biomarker	[20]
Neoplasm	DISZKGEW	Strong	Altered Expression	[21]
Obesity	DIS47Y1K	Strong	Biomarker	[22]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[8]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[23]
Stomach cancer	DISKIJSX	Strong	Biomarker	[17]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[7]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[7]
X-linked intellectual disability	DISYJBY3	Strong	Genetic Variation	[24]
Carcinoma	DISH9F1N	moderate	Altered Expression	[25]
Cervical carcinoma	DIST4S00	moderate	Altered Expression	[26]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[21]
Non-small-cell lung cancer	DIS5Y6R9	moderate	Altered Expression	[27]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[28]
Macular corneal dystrophy	DISOLD0H	Limited	Biomarker	[29]
Movement disorder	DISOJJ2D	Limited	CausalMutation	[28]
Pancreatic cancer	DISJC981	Limited	Altered Expression	[30]
Prostate cancer	DISF190Y	Limited	Altered Expression	[31]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[31]

12 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 Cullin-4B (CUL4B).	[32]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cullin-4B (CUL4B).	[33]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cullin-4B (CUL4B).	[34]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cullin-4B (CUL4B).	[35]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Cullin-4B (CUL4B).	[36]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Cullin-4B (CUL4B).	[37]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Cullin-4B (CUL4B).	[38]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Cullin-4B (CUL4B).	[39]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cullin-4B (CUL4B).	[40]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cullin-4B (CUL4B).	[41]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cullin-4B (CUL4B).	[44]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Cullin-4B (CUL4B).	[45]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Cullin-4B (CUL4B).	[42]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Cullin-4B (CUL4B).	[43]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Cullin-4B (CUL4B).	[42]

References

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• [2] Abnormal level of CUL4B-mediated histone H2A ubiquitination causes disruptive HOX gene expression.Epigenetics Chromatin. 2019 Apr 16;12(1):22. doi: 10.1186/s13072-019-0268-7.
• [3] Inflammation-dependent downregulation of miR-194-5p contributes to human intervertebral disc degeneration by targeting CUL4A and CUL4B.J Cell Physiol. 2019 Nov;234(11):19977-19989. doi: 10.1002/jcp.28595. Epub 2019 Apr 3.
• [4] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [5] Inflammation-dependent overexpression of c-Myc enhances CRL4(DCAF4) E3 ligase activity and promotes ubiquitination of ST7 in colitis-associated cancer.J Pathol. 2019 Aug;248(4):464-475. doi: 10.1002/path.5273. Epub 2019 Apr 22.
• [6] CUL4B regulates autophagy via JNK signaling in diffuse large B-cell lymphoma.Cell Cycle. 2019 Feb;18(4):379-394. doi: 10.1080/15384101.2018.1560718. Epub 2019 Feb 1.
• [7] CUL4B promotes bladder cancer metastasis and induces epithelial-to-mesenchymal transition by activating the Wnt/-catenin signaling pathway.Oncotarget. 2017 Aug 24;8(44):77241-77253. doi: 10.18632/oncotarget.20455. eCollection 2017 Sep 29.
• [8] Small molecule TSC01682 inhibits osteosarcoma cell growth by specifically disrupting the CUL4B-DDB1 interaction and decreasing the ubiquitination of CRL4B E3 ligase substrates.Am J Cancer Res. 2019 Sep 1;9(9):1857-1870. eCollection 2019.
• [9] 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.
• [10] Deletion of the CUL4B gene in a boy with mental retardation, minor facial anomalies, short stature, hypogonadism, and ataxia.Am J Med Genet A. 2010 Jan;152A(1):175-80. doi: 10.1002/ajmg.a.33152.
• [11] Cul4B is a novel prognostic marker in cholangiocarcinoma.Oncol Lett. 2017 Aug;14(2):1265-1274. doi: 10.3892/ol.2017.6297. Epub 2017 Jun 1.
• [12] Cullin 4B is a novel prognostic marker that correlates with colon cancer progression and pathogenesis.Med Oncol. 2013;30(2):534. doi: 10.1007/s12032-013-0534-7. Epub 2013 May 7.
• [13] Knockdown of CUL4B inhibits proliferation and promotes apoptosis of colorectal cancer cells through suppressing the Wnt/-catenin signaling pathway.Int J Clin Exp Pathol. 2015 Sep 1;8(9):10394-402. eCollection 2015.
• [14] Rescue of the genetically engineered Cul4b mutant mouse as a potential model for human X-linked mental retardation.Hum Mol Genet. 2012 Oct 1;21(19):4270-85. doi: 10.1093/hmg/dds261. Epub 2012 Jul 3.
• [15] MicroRNA-133b inhibits cell proliferation and promotes apoptosis by targeting cullin 4B in esophageal squamous cell carcinoma.Exp Ther Med. 2018 Apr;15(4):3743-3750. doi: 10.3892/etm.2018.5906. Epub 2018 Feb 28.
• [16] CRL4 ubiquitin ligase stimulates Fanconi anemia pathway-induced single-stranded DNA-RPA signaling.BMC Cancer. 2019 Nov 5;19(1):1042. doi: 10.1186/s12885-019-6305-x.
• [17] miR?81 and miR?89 suppress cell proliferation and invasion by targeting CUL4B via the Wnt/catenin pathway in gastric cancer.Int J Oncol. 2019 Feb;54(2):733-743. doi: 10.3892/ijo.2018.4646. Epub 2018 Nov 26.
• [18] CUL4B activates Wnt/-catenin signalling in hepatocellular carcinoma by repressing Wnt antagonists.J Pathol. 2015 Apr;235(5):784-95. doi: 10.1002/path.4492. Epub 2015 Jan 23.
• [19] NCBP1 promotes the development of lung adenocarcinoma through up-regulation of CUL4B.J Cell Mol Med. 2019 Oct;23(10):6965-6977. doi: 10.1111/jcmm.14581. Epub 2019 Aug 26.
• [20] Dysregulation of the miR-194-CUL4B negative feedback loop drives tumorigenesis in non-small-cell lung carcinoma.Mol Oncol. 2017 Mar;11(3):305-319. doi: 10.1002/1878-0261.12038. Epub 2017 Feb 21.
• [21] CUL4B promotes aggressive phenotypes of HNSCC via the activation of the Wnt/-catenin signaling pathway.Cancer Med. 2019 May;8(5):2278-2287. doi: 10.1002/cam4.1960. Epub 2019 Mar 18.
• [22] Lack of CUL4B in Adipocytes Promotes PPAR-Mediated Adipose Tissue Expansion and Insulin Sensitivity.Diabetes. 2017 Feb;66(2):300-313. doi: 10.2337/db16-0743. Epub 2016 Nov 29.
• [23] Mutations in Cullin 4B result in a human syndrome associated with increased camptothecin-induced topoisomerase I-dependent DNA breaks.Hum Mol Genet. 2010 Apr 1;19(7):1324-34. doi: 10.1093/hmg/ddq008. Epub 2010 Jan 11.
• [24] Lack of Cul4b, an E3 ubiquitin ligase component, leads to embryonic lethality and abnormal placental development.PLoS One. 2012;7(5):e37070. doi: 10.1371/journal.pone.0037070. Epub 2012 May 14.
• [25] Dysregulation of CUL4A and CUL4B Ubiquitin Ligases in Lung Cancer.J Biol Chem. 2017 Feb 17;292(7):2966-2978. doi: 10.1074/jbc.M116.765230. Epub 2016 Dec 14.
• [26] CRL4B promotes tumorigenesis by coordinating with SUV39H1/HP1/DNMT3A in DNA methylation-based epigenetic silencing.Oncogene. 2015 Jan 2;34(1):104-18. doi: 10.1038/onc.2013.522. Epub 2013 Dec 2.
• [27] Circular RNA ZFR accelerates non-small cell lung cancer progression by acting as a miR-101-3p sponge to enhance CUL4B expression.Artif Cells Nanomed Biotechnol. 2019 Dec;47(1):3410-3416. doi: 10.1080/21691401.2019.1652623.
• [28] A new CUL4B variant associated with a mild phenotype and an exceptional pattern of leukoencephalopathy.Am J Med Genet A. 2017 Oct;173(10):2803-2807. doi: 10.1002/ajmg.a.38390. Epub 2017 Aug 17.
• [29] Variants in CUL4B are associated with cerebral malformations.Hum Mutat. 2015 Jan;36(1):106-17. doi: 10.1002/humu.22718.
• [30] MicroRNA-300 promotes apoptosis and inhibits proliferation, migration, invasion and epithelial-mesenchymal transition via the Wnt/-catenin signaling pathway by targeting CUL4B in pancreatic cancer cells.J Cell Biochem. 2018 Jan;119(1):1027-1040. doi: 10.1002/jcb.26270. Epub 2017 Aug 23.
• [31] CUL4B promotes prostate cancer progression by forming positive feedback loop with SOX4.Oncogenesis. 2019 Mar 14;8(3):23. doi: 10.1038/s41389-019-0131-5.
• [32] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [33] 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.
• [34] 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.
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• [36] Analysis of the in vitro synergistic effect of 5-fluorouracil and cisplatin on cervical carcinoma cells. Int J Gynecol Cancer. 2006 May-Jun;16(3):1321-9.
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• [38] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [39] Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem. 2004 Mar;88(5):1211-9. doi: 10.1046/j.1471-4159.2003.02247.x.
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• [41] 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.
• [42] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
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