Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMD6IM2)

• DOT Name: E3 ubiquitin-protein ligase TRIM11 (TRIM11)
• Synonyms: EC 2.3.2.27; Protein BIA1; RING finger protein 92; Tripartite motif-containing protein 11
• Gene Name: TRIM11
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Central hypoventilation syndrome, congenital
  Chordoma
  Clear cell sarcoma
  Colon cancer
  Colon carcinoma
  Diabetic kidney disease
  Glioma
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Malignant glioma
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  B-cell neoplasm
  Lung cancer
  Lung carcinoma
  Lymphoma
  Progressive supranuclear palsy
• UniProt ID: TRI11_HUMAN
• PDB ID: 7QS1
• EC Number: 2.3.2.27
• Pfam ID: PF13765 ; PF00622 ; PF00643 ; PF15227
• Sequence:
  MAAPDLSTNLQEEATCAICLDYFTDPVMTDCGHNFCRECIRRCWGQPEGPYACPECRELS
  PQRNLRPNRPLAKMAEMARRLHPPSPVPQGVCPAHREPLAAFCGDELRLLCAACERSGEH
  WAHRVRPLQDAAEDLKAKLEKSLEHLRKQMQDALLFQAQADETCVLWQKMVESQRQNVLG
  EFERLRRLLAEEEQQLLQRLEEEELEVLPRLREGAAHLGQQSAHLAELIAELEGRCQLPA
  LGLLQDIKDALRRVQDVKLQPPEVVPMELRTVCRVPGLVETLRRFRGDVTLDPDTANPEL
  ILSEDRRSVQRGDLRQALPDSPERFDPGPCVLGQERFTSGRHYWEVEVGDRTSWALGVCR
  ENVNRKEKGELSAGNGFWILVFLGSYYNSSERALAPLRDPPRRVGIFLDYEAGHLSFYSA
  TDGSLLFIFPEIPFSGTLRPLFSPLSSSPTPMTICRPKGGSGDTLAPQ
• Function: E3 ubiquitin-protein ligase that promotes the degradation of insoluble ubiquitinated proteins, including insoluble PAX6, poly-Gln repeat expanded HTT and poly-Ala repeat expanded ARX. Mediates PAX6 ubiquitination leading to proteasomal degradation, thereby modulating cortical neurogenesis. May also inhibit PAX6 transcriptional activity, possibly in part by preventing the binding of PAX6 to its consensus sequences. May contribute to the regulation of the intracellular level of HN (humanin) or HN-containing proteins through the proteasomal degradation pathway. Mediates MED15 ubiquitination leading to proteasomal degradation. May contribute to the innate restriction of retroviruses. Upon overexpression, reduces HIV-1 and murine leukemia virus infectivity, by suppressing viral gene expression. Antiviral activity depends on a functional E3 ubiquitin-protein ligase domain. May regulate TRIM5 turnover via the proteasome pathway, thus counteracting the TRIM5-mediated cross-species restriction of retroviral infection at early stages of the retroviral life cycle. Acts as an inhibitor of the AIM2 inflammasome by promoting autophagy-dependent degradation of AIM2. Mechanistically, undergoes autoubiquitination upon DNA stimulation, promoting interaction with AIM2 and SQSTM1/p62, leading to AIM2 recruitment to autophagosomes.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Central hypoventilation syndrome, congenital	DISQRK53	Strong	Biomarker	[3]
Chordoma	DISCHJE7	Strong	Biomarker	[4]
Clear cell sarcoma	DIS1MTE6	Strong	Genetic Variation	[5]
Colon cancer	DISVC52G	Strong	Biomarker	[6]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[6]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[7]
Glioma	DIS5RPEH	Strong	Altered Expression	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[9]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[10]
Malignant glioma	DISFXKOV	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Prostate cancer	DISF190Y	Strong	Biomarker	[11]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[11]
B-cell neoplasm	DISVY326	Limited	Altered Expression	[2]
Lung cancer	DISCM4YA	Limited	Biomarker	[2]
Lung carcinoma	DISTR26C	Limited	Biomarker	[2]
Lymphoma	DISN6V4S	Limited	Biomarker	[12]
Progressive supranuclear palsy	DISO5KRQ	Limited	Genetic Variation	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of E3 ubiquitin-protein ligase TRIM11 (TRIM11).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase TRIM11 (TRIM11).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase TRIM11 (TRIM11).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase TRIM11 (TRIM11).	[16]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of E3 ubiquitin-protein ligase TRIM11 (TRIM11).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase TRIM11 (TRIM11).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase TRIM11 (TRIM11).	[20]

References

• [1] TRIM11 is overexpressed in high-grade gliomas and promotes proliferation, invasion, migration and glial tumor growth.Oncogene. 2013 Oct 17;32(42):5038-47. doi: 10.1038/onc.2012.531. Epub 2012 Nov 26.
• [2] Tripartite motifcontaining11 regulates the proliferation and apoptosis of breast cancer cells.Oncol Rep. 2019 Apr;41(4):2567-2574. doi: 10.3892/or.2019.7015. Epub 2019 Feb 14.
• [3] The E3 ubiquitin ligase TRIM11 mediates the degradation of congenital central hypoventilation syndrome-associated polyalanine-expanded PHOX2B.J Mol Med (Berl). 2012 Sep;90(9):1025-35. doi: 10.1007/s00109-012-0868-1. Epub 2012 Feb 4.
• [4] Silencing of TRIM11 suppresses the tumorigenicity of chordoma cells through improving the activity of PHLPP1/AKT.Cancer Cell Int. 2019 Nov 8;19:284. doi: 10.1186/s12935-019-1007-7. eCollection 2019.
• [5] A case report of cutaneous melanocytoma with CRTC1-TRIM11 fusion: Is CMCT distinct from clear cell sarcoma of soft tissue?.Pathol Int. 2019 Aug;69(8):496-501. doi: 10.1111/pin.12826. Epub 2019 Jul 5.
• [6] TRIM11, a direct target of miR-24-3p, promotes cell proliferation and inhibits apoptosis in colon cancer.Oncotarget. 2016 Dec 27;7(52):86755-86765. doi: 10.18632/oncotarget.13550.
• [7] The topological key lncRNA H2k2 from the ceRNA network promotes mesangial cell proliferation in diabetic nephropathy via the miR-449a/b/Trim11/Mek signaling pathway.FASEB J. 2019 Oct;33(10):11492-11506. doi: 10.1096/fj.201900522R. Epub 2019 Jul 23.
• [8] TRIM11 overexpression promotes proliferation, migration and invasion of lung cancer cells.J Exp Clin Cancer Res. 2016 Jun 21;35(1):100. doi: 10.1186/s13046-016-0379-y.
• [9] TRIM11 Upregulation Contributes to Proliferation, Invasion, and EMT of Hepatocellular Carcinoma Cells.Oncol Res. 2017 May 24;25(5):691-699. doi: 10.3727/096504016X14774897404770. Epub 2016 Dec 15.
• [10] TRIM11 promotes tumor angiogenesis via activation of STAT3/VEGFA signaling in lung adenocarcinoma.Am J Cancer Res. 2019 Sep 1;9(9):2019-2027. eCollection 2019.
• [11] Expression of Tripartite Motif-Containing Proteactiin 11 (TRIM11) is Associated with the Progression of Human Prostate Cancer and is Downregulated by MicroRNA-5193.Med Sci Monit. 2019 Jan 4;25:98-106. doi: 10.12659/MSM.911818.
• [12] TRIM11 promotes lymphomas by activating the -catenin signaling and Axin1 ubiquitination degradation.Exp Cell Res. 2020 Feb 15;387(2):111750. doi: 10.1016/j.yexcr.2019.111750. Epub 2019 Nov 28.
• [13] Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype.Ann Neurol. 2018 Oct;84(4):485-496. doi: 10.1002/ana.25308. Epub 2018 Sep 15.
• [14] 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.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] 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.
• [20] 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.