Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYA1UIO)

• DOT Name: E3 ubiquitin-protein ligase RBX1 (RBX1)
• Synonyms: EC 2.3.2.27; EC 2.3.2.32; E3 ubiquitin-protein transferase RBX1; Protein ZYP; RING finger protein 75; RING-box protein 1; Rbx1; Regulator of cullins 1; ROC1
• Gene Name: RBX1
• Related Disease:
  Bladder transitional cell carcinoma
  Advanced cancer
  Anxiety
  Bladder cancer
  Breast carcinoma
  Carcinoma of esophagus
  Crohn disease
  Esophageal cancer
  Gastric cancer
  Gastric neoplasm
  Head and neck cancer
  Head and neck carcinoma
  Head-neck squamous cell carcinoma
  Neoplasm of esophagus
  Non-small-cell lung cancer
  Persistent truncus arteriosus
  Polycythemia
  Prostate carcinoma
  Renal cell carcinoma
  Stevens-Johnson syndrome
  Stomach cancer
  Toxic epidermal necrolysis
  Transitional cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Von hippel-lindau disease
  Kidney cancer
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid gland papillary carcinoma
  Thyroid tumor
  Epithelial ovarian cancer
  Melanoma
  Ovarian cancer
  Ovarian neoplasm
  Carcinoma of liver and intrahepatic biliary tract
  Castration-resistant prostate carcinoma
  Clear cell renal carcinoma
  Cutaneous melanoma
  Glomuvenous malformation
  Hepatocellular carcinoma
  Liver cancer
  Melanocytic nevus
  Neuroblastoma
• UniProt ID: RBX1_HUMAN
• PDB ID: 1LDJ ; 1LDK ; 1U6G ; 2HYE ; 2LGV ; 3DPL ; 3DQV ; 3RTR ; 4F52 ; 4P5O ; 5N4W ; 6R6H ; 6R7F ; 6R7H ; 6R7I ; 6R7N ; 6TTU ; 7B5L ; 7B5M ; 7B5N ; 7B5S ; 7OKQ ; 7PLO ; 7Z8B ; 7Z8R ; 7Z8T ; 7Z8V ; 7ZBW ; 8B3I ; 8CDJ ; 8CDK ; 8GQ6 ; 8H33 ; 8H34 ; 8H35 ; 8H36 ; 8H37 ; 8H38 ; 8H3A ; 8H3F ; 8H3Q ; 8H3R ; 8JAQ ; 8JAS ; 8JAV ; 8OR0 ; 8OR2 ; 8OR3 ; 8OR4 ; 8QU8
• EC Number: 2.3.2.27; 2.3.2.32
• Pfam ID: PF12678
• Sequence:
  MAAAMDVDTPSGTNSGAGKKRFEVKKWNAVALWAWDIVVDNCAICRNHIMDLCIECQANQ
  ASATSEECTVAWGVCNHAFHFHCISRWLKTRQVCPLDNREWEFQKYGH
• Function: E3 ubiquitin ligase component of multiple cullin-RING-based E3 ubiquitin-protein ligase (CRLs) complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins, including proteins involved in cell cycle progression, signal transduction, transcription and transcription-coupled nucleotide excision repair. CRLs complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins, ARIH1 mediating addition of the first ubiquitin on CRLs targets. The functional specificity of the E3 ubiquitin-protein ligase complexes depends on the variable substrate recognition components. As a component of the CSA complex promotes the ubiquitination of ERCC6 resulting in proteasomal degradation. Recruits the E2 ubiquitin-conjugating enzyme CDC34 to the complex and brings it into close proximity to the substrate. Probably also stimulates CDC34 autoubiquitination. May be required for histone H3 and histone H4 ubiquitination in response to ultraviolet and for subsequent DNA repair. Promotes the neddylation of CUL1, CUL2, CUL4 and CUL4 via its interaction with UBE2M. Involved in the ubiquitination of KEAP1, ENC1 and KLHL41. In concert with ATF2 and CUL3, promotes degradation of KAT5 thereby attenuating its ability to acetylate and activate ATM. As part of a multisubunit complex composed of elongin BC complex (ELOB and ELOC), elongin A/ELOA, RBX1 and CUL5; polyubiquitinates monoubiquitinated POLR2A.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Nucleotide excision repair (hsa03420)
  HIF-1 sig.ling pathway (hsa04066)
  Cell cycle (hsa04110)
  Oocyte meiosis (hsa04114)
  Ubiquitin mediated proteolysis (hsa04120)
  Protein processing in endoplasmic reticulum (hsa04141)
  Wnt sig.ling pathway (hsa04310)
  TGF-beta sig.ling pathway (hsa04350)
  Circadian rhythm (hsa04710)
  Shigellosis (hsa05131)
  Human immunodeficiency virus 1 infection (hsa05170)
  Pathways in cancer (hsa05200)
  Re.l cell carcinoma (hsa05211)
• Reactome Pathway:
  Prolactin receptor signaling (R-HSA-1170546)
  Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha (R-HSA-1234176)
  Vif-mediated degradation of APOBEC3G (R-HSA-180585)
  Degradation of beta-catenin by the destruction complex (R-HSA-195253)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling (R-HSA-2644607)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  Degradation of DVL (R-HSA-4641258)
  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)
  Hedgehog 'on' state (R-HSA-5632684)
  Regulation of RAS by GAPs (R-HSA-5658442)
  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)
  Orc1 removal from chromatin (R-HSA-68949)
  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)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Interleukin-1 signaling (R-HSA-9020702)
  Negative regulation of NOTCH4 signaling (R-HSA-9604323)
  Potential therapeutics for SARS (R-HSA-9679191)
  Regulation of BACH1 activity (R-HSA-9708530)
  Nuclear events stimulated by ALK signaling in cancer (R-HSA-9725371)
  KEAP1-NFE2L2 pathway (R-HSA-9755511)
  GSK3B and BTRC (R-HSA-9762114)
  Antigen processing (R-HSA-983168)
  Recognition of DNA damage by PCNA-containing replication complex (R-HSA-110314)

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder transitional cell carcinoma	DISNL46A	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Anxiety	DISIJDBA	Strong	Genetic Variation	[3]
Bladder cancer	DISUHNM0	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[5]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[6]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	Strong	Biomarker	[7]
Gastric neoplasm	DISOKN4Y	Strong	Altered Expression	[8]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[9]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[9]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[9]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Persistent truncus arteriosus	DISRZ8EA	Strong	Altered Expression	[11]
Polycythemia	DIS8B6VW	Strong	Biomarker	[12]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[13]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[14]
Stevens-Johnson syndrome	DISZG4YX	Strong	Biomarker	[15]
Stomach cancer	DISKIJSX	Strong	Biomarker	[7]
Toxic epidermal necrolysis	DISIWPFR	Strong	Biomarker	[15]
Transitional cell carcinoma	DISWVVDR	Strong	Biomarker	[2]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[2]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Biomarker	[12]
Kidney cancer	DISBIPKM	moderate	Altered Expression	[14]
Thyroid cancer	DIS3VLDH	moderate	Biomarker	[16]
Thyroid gland carcinoma	DISMNGZ0	moderate	Biomarker	[16]
Thyroid gland papillary carcinoma	DIS48YMM	moderate	Biomarker	[16]
Thyroid tumor	DISLVKMD	moderate	Biomarker	[16]
Epithelial ovarian cancer	DIS56MH2	Disputed	Biomarker	[17]
Melanoma	DIS1RRCY	Disputed	Altered Expression	[18]
Ovarian cancer	DISZJHAP	Disputed	Biomarker	[17]
Ovarian neoplasm	DISEAFTY	Disputed	Biomarker	[17]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Altered Expression	[19]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Biomarker	[20]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[14]
Cutaneous melanoma	DIS3MMH9	Limited	Altered Expression	[21]
Glomuvenous malformation	DIS5UNDD	Limited	Altered Expression	[22]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[23]
Liver cancer	DISDE4BI	Limited	Altered Expression	[19]
Melanocytic nevus	DISYS32D	Limited	Altered Expression	[21]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[24]

18 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 E3 ubiquitin-protein ligase RBX1 (RBX1).	[25]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of E3 ubiquitin-protein ligase RBX1 (RBX1).	[26]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase RBX1 (RBX1).	[27]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase RBX1 (RBX1).	[28]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of E3 ubiquitin-protein ligase RBX1 (RBX1).	[29]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of E3 ubiquitin-protein ligase RBX1 (RBX1).	[30]
Marinol	DM70IK5	Approved	Marinol increases the expression of E3 ubiquitin-protein ligase RBX1 (RBX1).	[31]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of E3 ubiquitin-protein ligase RBX1 (RBX1).	[32]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of E3 ubiquitin-protein ligase RBX1 (RBX1).	[33]
Sertraline	DM0FB1J	Approved	Sertraline decreases the expression of E3 ubiquitin-protein ligase RBX1 (RBX1).	[34]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of E3 ubiquitin-protein ligase RBX1 (RBX1).	[35]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of E3 ubiquitin-protein ligase RBX1 (RBX1).	[36]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of E3 ubiquitin-protein ligase RBX1 (RBX1).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of E3 ubiquitin-protein ligase RBX1 (RBX1).	[39]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of E3 ubiquitin-protein ligase RBX1 (RBX1).	[40]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of E3 ubiquitin-protein ligase RBX1 (RBX1).	[41]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of E3 ubiquitin-protein ligase RBX1 (RBX1).	[42]
Okadaic acid	DM47CO1	Investigative	Okadaic acid increases the expression of E3 ubiquitin-protein ligase RBX1 (RBX1).	[43]

1 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 decreases the phosphorylation of E3 ubiquitin-protein ligase RBX1 (RBX1).	[38]

References

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