Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0PR1X5)

• DOT Name: E3 ubiquitin-protein ligase RNF139 (RNF139)
• Synonyms: EC 2.3.2.27; RING finger protein 139; RING-type E3 ubiquitin transferase RNF139; Translocation in renal carcinoma on chromosome 8 protein
• Gene Name: RNF139
• Related Disease:
  Kidney cancer
  Renal carcinoma
  Barrett esophagus
  Glioblastoma multiforme
  Hemangioblastoma
  Hepatitis C virus infection
  Hereditary renal cell carcinoma
  Immunodeficiency
  Krabbe disease
  Medullary thyroid gland carcinoma
  Neoplasm
  Oral cancer
  Renal cell carcinoma
  Thyroid cancer
  Thyroid gland carcinoma
  Clear cell renal carcinoma
  Advanced cancer
  Nonpapillary renal cell carcinoma
• UniProt ID: RN139_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF13705 ; PF13639
• Sequence:
  MAAVGPPQQQVRMAHQQVWAALEVALRVPCLYIIDAIFNSYPDSSQSRFCIVLQIFLRLF
  GVFASSIVLILSQRSLFKFYTYSSAFLLAATSVLVNYYASLHIDFYGAYNTSAFGIELLP
  RKGPSLWMALIVLQLTFGIGYVTLLQIHSIYSQLIILDLLVPVIGLITELPLHIRETLLF
  TSSLILTLNTVFVLAVKLKWFYYSTRYVYLLVRHMYRIYGLQLLMEDTWKRIRFPDILRV
  FWLTRVTAQATVLMYILRMANETDSFFISWDDFWDLICNLIISGCDSTLTVLGMSAVISS
  VAHYLGLGILAFIGSTEEDDRRLGFVAPVLFFILALQTGLSGLRPEERLIRLSRNMCLLL
  TAVLHFIHGMTDPVLMSLSASHVSSFRRHFPVLFVSACLFILPVLLSYVLWHHYALNTWL
  FAVTAFCVELCLKVIVSLTVYTLFMIDGYYNVLWEKLDDYVYYVRSTGSIIEFIFGVVMF
  GNGAYTMMFESGSKIRAFMMCLHAYFNIYLQAKNGWKTFMNRRTAVKKINSLPEIKGSRL
  QEINDVCAICYHEFTTSARITPCNHYFHALCLRKWLYIQDTCPMCHQKVYIEDDIKDNSN
  VSNNNGFIPPNETPEEAVREAAAESDRELNEDDSTDCDDDVQRERNGVIQHTGAAAEEFN
  DDTD
• Function: E3-ubiquitin ligase; acts as a negative regulator of cell proliferation through mechanisms involving G2/M arrest and cell death. Required for MHC class I ubiquitination in cells expressing the cytomegalovirus protein US2 before dislocation from the endoplasmic reticulum (ER). Affects SREBP processing by hindering the SREBP-SCAP complex translocation from the ER to the Golgi, thereby reducing SREBF2 target gene expression. Involved in the sterol-accelerated degradation of HMGCR. This is achieved through binding of RNF139 to INSIG1 and/or INSIG2 at the ER membrane. In addition, interaction of RNF139 with AUP1 facilitates interaction of RNF139 with ubiquitin-conjugating enzyme UBE2G2 and ubiquitin ligase AMFR, leading to ubiquitination of HMGCR. The ubiquitinated HMGCR is then released from the ER into the cytosol for subsequent destruction. Required for INSIG1 ubiquitination. May be required for EIF3 complex ubiquitination.
• Tissue Specificity: Highly expressed in testis, placenta and adrenal gland. Moderate expression in heart, brain, liver, skeletal muscle and pancreas, and low expression in lung and kidney.
• Reactome Pathway: ER Quality Control Compartment (ERQC) (R-HSA-901032)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Kidney cancer	DISBIPKM	Definitive	Genetic Variation	[1]
Renal carcinoma	DISER9XT	Definitive	Genetic Variation	[1]
Barrett esophagus	DIS416Y7	Strong	Altered Expression	[2]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Hemangioblastoma	DIS1EAZC	Strong	Genetic Variation	[4]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[5]
Hereditary renal cell carcinoma	DISTN8X8	Strong	Biomarker	[6]
Immunodeficiency	DIS093I0	Strong	Biomarker	[7]
Krabbe disease	DIS6H1IB	Strong	Biomarker	[8]
Medullary thyroid gland carcinoma	DISHBL3K	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[10]
Oral cancer	DISLD42D	Strong	Biomarker	[7]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[6]
Thyroid cancer	DIS3VLDH	Strong	Biomarker	[3]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[3]
Clear cell renal carcinoma	DISBXRFJ	Disputed	Genetic Variation	[11]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[1]
Nonpapillary renal cell carcinoma	DISGFURW	No Known	Unknown	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of E3 ubiquitin-protein ligase RNF139 (RNF139).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase RNF139 (RNF139).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of E3 ubiquitin-protein ligase RNF139 (RNF139).	[15]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of E3 ubiquitin-protein ligase RNF139 (RNF139).	[16]
Marinol	DM70IK5	Approved	Marinol decreases the expression of E3 ubiquitin-protein ligase RNF139 (RNF139).	[17]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of E3 ubiquitin-protein ligase RNF139 (RNF139).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase RNF139 (RNF139).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of E3 ubiquitin-protein ligase RNF139 (RNF139).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of E3 ubiquitin-protein ligase RNF139 (RNF139).	[21]

References

• [1] TRC8 suppresses tumorigenesis through targeting heme oxygenase-1 for ubiquitination and degradation.Oncogene. 2013 May 2;32(18):2325-34. doi: 10.1038/onc.2012.244. Epub 2012 Jun 11.
• [2] RING finger proteins are involved in the progression of barrett esophagus to esophageal adenocarcinoma: a preliminary study.Gut Liver. 2014 Sep;8(5):487-94. doi: 10.5009/gnl13133. Epub 2014 Feb 24.
• [3] The tumor suppressor gene TRC8/RNF139 is disrupted by a constitutional balanced translocation t(8;22)(q24.13;q11.21) in a young girl with dysgerminoma.Mol Cancer. 2009 Jul 30;8:52. doi: 10.1186/1476-4598-8-52.
• [4] A Novel RNF139 Mutation in Hemangioblastomas: Case Report.Front Neurol. 2019 Apr 12;10:359. doi: 10.3389/fneur.2019.00359. eCollection 2019.
• [5] TRC8-dependent degradation of hepatitis C virus immature core protein regulates viral propagation and pathogenesis.Nat Commun. 2016 May 4;7:11379. doi: 10.1038/ncomms11379.
• [6] Growth suppression induced by the TRC8 hereditary kidney cancer gene is dependent upon JAB1/CSN5.Oncogene. 2005 May 12;24(21):3503-11. doi: 10.1038/sj.onc.1208509.
• [7] E3 ubiquitin ligase, RNF139, inhibits the progression of tongue cancer.BMC Cancer. 2017 Jun 29;17(1):452. doi: 10.1186/s12885-017-3438-7.
• [8] Immuno-lectin histochemistry and ultrastructure in two cases of globoid cell leukodystrophy (Krabbe's disease).Clin Neuropathol. 1992 Nov-Dec;11(6):312-7.
• [9] The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway.Oncogene. 2002 May 16;21(22):3507-16. doi: 10.1038/sj.onc.1205437.
• [10] Constitutional t(8;22)(q24;q11.2) that mimics the variant Burkitt-type translocation in Philadelphia chromosome-positive chronic myeloid leukemia.Int J Hematol. 2017 Feb;105(2):226-229. doi: 10.1007/s12185-016-2100-5. Epub 2016 Sep 29.
• [11] A constitutional balanced t(3;8)(p14;q24.1) translocation results in disruption of the TRC8 gene and predisposition to clear cell renal cell carcinoma.Genes Chromosomes Cancer. 2007 Sep;46(9):805-12. doi: 10.1002/gcc.20466.
• [12] The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8. Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9572-7. doi: 10.1073/pnas.95.16.9572.
• [13] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [14] 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.
• [15] Sex hormones and gene expression signatures in peripheral blood from postmenopausal women - the NOWAC postgenome study. BMC Med Genomics. 2011 Mar 31;4:29. doi: 10.1186/1755-8794-4-29.
• [16] 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.
• [17] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [18] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [21] 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.