Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0KS4J7)

• DOT Name: E3 ubiquitin-protein ligase TRIM33 (TRIM33)
• Synonyms: EC 2.3.2.27; Ectodermin homolog; RET-fused gene 7 protein; Protein Rfg7; RING-type E3 ubiquitin transferase TRIM33; Transcription intermediary factor 1-gamma; TIF1-gamma; Tripartite motif-containing protein 33
• Gene Name: TRIM33
• Related Disease:
  Hepatocellular carcinoma
  Autoimmune disease
  Chagas disease
  Childhood myelodysplastic syndrome
  Classic Hodgkin lymphoma
  Clear cell renal carcinoma
  Head-neck squamous cell carcinoma
  Myelodysplastic syndrome
  Myositis disease
  Non-small-cell lung cancer
  Pancreatic tumour
  Polymyositis
  Prostate carcinoma
  Renal cell carcinoma
  Small lymphocytic lymphoma
  Thrombocytopenia
  Thyroid gland papillary carcinoma
  Autism
  Bacterial infection
  Acute lymphocytic leukaemia
  Breast cancer
  Breast carcinoma
  Chronic myelomonocytic leukaemia
  Chronic myelomonocytic leukemia
  Idiopathic inflammatory myopathy
  Lymphoid leukemia
  Myeloproliferative neoplasm
  Myotonic dystrophy type 1
  Type-1/2 diabetes
• UniProt ID: TRI33_HUMAN
• PDB ID: 3U5M; 3U5N; 3U5O; 3U5P; 5MR8; 7ZDD; 8BD8; 8BD9; 8BDY
• EC Number: 2.3.2.27
• Pfam ID: PF00439 ; PF00628 ; PF00643
• Sequence:
  MAENKGGGEAESGGGGSGSAPVTAGAAGPAAQEAEPPLTAVLVEEEEEEGGRAGAEGGAA
  GPDDGGVAAASSGSAQAASSPAASVGTGVAGGAVSTPAPAPASAPAPGPSAGPPPGPPAS
  LLDTCAVCQQSLQSRREAEPKLLPCLHSFCLRCLPEPERQLSVPIPGGSNGDIQQVGVIR
  CPVCRQECRQIDLVDNYFVKDTSEAPSSSDEKSEQVCTSCEDNASAVGFCVECGEWLCKT
  CIEAHQRVKFTKDHLIRKKEDVSESVGASGQRPVFCPVHKQEQLKLFCETCDRLTCRDCQ
  LLEHKEHRYQFLEEAFQNQKGAIENLLAKLLEKKNYVHFAATQVQNRIKEVNETNKRVEQ
  EIKVAIFTLINEINKKGKSLLQQLENVTKERQMKLLQQQNDITGLSRQVKHVMNFTNWAI
  ASGSSTALLYSKRLITFQLRHILKARCDPVPAANGAIRFHCDPTFWAKNVVNLGNLVIES
  KPAPGYTPNVVVGQVPPGTNHISKTPGQINLAQLRLQHMQQQVYAQKHQQLQQMRMQQPP
  APVPTTTTTTQQHPRQAAPQMLQQQPPRLISVQTMQRGNMNCGAFQAHQMRLAQNAARIP
  GIPRHSGPQYSMMQPHLQRQHSNPGHAGPFPVVSVHNTTINPTSPTTATMANANRGPTSP
  SVTAIELIPSVTNPENLPSLPDIPPIQLEDAGSSSLDNLLSRYISGSHLPPQPTSTMNPS
  PGPSALSPGSSGLSNSHTPVRPPSTSSTGSRGSCGSSGRTAEKTSLSFKSDQVKVKQEPG
  TEDEICSFSGGVKQEKTEDGRRSACMLSSPESSLTPPLSTNLHLESELDALASLENHVKI
  EPADMNESCKQSGLSSLVNGKSPIRSLMHRSARIGGDGNNKDDDPNEDWCAVCQNGGDLL
  CCEKCPKVFHLTCHVPTLLSFPSGDWICTFCRDIGKPEVEYDCDNLQHSKKGKTAQGLSP
  VDQRKCERLLLYLYCHELSIEFQEPVPASIPNYYKIIKKPMDLSTVKKKLQKKHSQHYQI
  PDDFVADVRLIFKNCERFNEMMKVVQVYADTQEINLKADSEVAQAGKAVALYFEDKLTEI
  YSDRTFAPLPEFEQEEDDGEVTEDSDEDFIQPRRKRLKSDERPVHIK
• Function: Acts as an E3 ubiquitin-protein ligase. Promotes SMAD4 ubiquitination, nuclear exclusion and degradation via the ubiquitin proteasome pathway. According to PubMed:16751102, does not promote a decrease in the level of endogenous SMAD4. May act as a transcriptional repressor. Inhibits the transcriptional response to TGF-beta/BMP signaling cascade. Plays a role in the control of cell proliferation. Its association with SMAD2 and SMAD3 stimulates erythroid differentiation of hematopoietic stem/progenitor. Monoubiquitinates SMAD4 and acts as an inhibitor of SMAD4-dependent TGF-beta/BMP signaling cascade (Monoubiquitination of SMAD4 hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade).
• Tissue Specificity: Expressed in stem cells at the bottom of the crypts of the colon (at protein level). Expressed in colon adenomas and adenocarcinomas (at protein level). Expressed in brain, lung, liver, spleen, thymus, prostate, kidney, testis, heart, placenta, pancreas, small intestine, ovary, colon, skeletal muscle and hematopoietic progenitors.
• Reactome Pathway:
  Germ layer formation at gastrulation (R-HSA-9754189)
  Downregulation of SMAD2/3 (R-HSA-2173795)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Altered Expression	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
Chagas disease	DIS8KNVF	Strong	Biomarker	[3]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Biomarker	[4]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[6]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[7]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[4]
Myositis disease	DISCIXF0	Strong	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[9]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[10]
Polymyositis	DIS5DHFP	Strong	Altered Expression	[8]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[11]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[6]
Small lymphocytic lymphoma	DIS30POX	Strong	Altered Expression	[12]
Thrombocytopenia	DISU61YW	Strong	Biomarker	[3]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Altered Expression	[13]
Autism	DISV4V1Z	moderate	Biomarker	[14]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[15]
Acute lymphocytic leukaemia	DISPX75S	Limited	Biomarker	[16]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[17]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[17]
Chronic myelomonocytic leukaemia	DISDN5P7	Limited	Biomarker	[18]
Chronic myelomonocytic leukemia	DISIL8UR	Limited	Biomarker	[18]
Idiopathic inflammatory myopathy	DISGB1BZ	Limited	Altered Expression	[19]
Lymphoid leukemia	DIS65TYQ	Limited	Biomarker	[16]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Genetic Variation	[18]
Myotonic dystrophy type 1	DISJC0OX	Limited	Altered Expression	[19]
Type-1/2 diabetes	DISIUHAP	Limited	Altered Expression	[19]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
(+)-JQ1	DM1CZSJ	Phase 1	E3 ubiquitin-protein ligase TRIM33 (TRIM33) decreases the response to substance of (+)-JQ1.	[33]

4 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 E3 ubiquitin-protein ligase TRIM33 (TRIM33).	[20]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of E3 ubiquitin-protein ligase TRIM33 (TRIM33).	[26]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of E3 ubiquitin-protein ligase TRIM33 (TRIM33).	[29]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of E3 ubiquitin-protein ligase TRIM33 (TRIM33).	[30]

10 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 TRIM33 (TRIM33).	[21]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of E3 ubiquitin-protein ligase TRIM33 (TRIM33).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase TRIM33 (TRIM33).	[23]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase TRIM33 (TRIM33).	[24]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of E3 ubiquitin-protein ligase TRIM33 (TRIM33).	[25]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of E3 ubiquitin-protein ligase TRIM33 (TRIM33).	[22]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of E3 ubiquitin-protein ligase TRIM33 (TRIM33).	[27]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of E3 ubiquitin-protein ligase TRIM33 (TRIM33).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of E3 ubiquitin-protein ligase TRIM33 (TRIM33).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of E3 ubiquitin-protein ligase TRIM33 (TRIM33).	[32]

References

• [1] Circular RNA circTRIM33-12 acts as the sponge of MicroRNA-191 to suppress hepatocellular carcinoma progression.Mol Cancer. 2019 Jun 1;18(1):105. doi: 10.1186/s12943-019-1031-1.
• [2] Trim33 mediates the proinflammatory function of Th17 cells.J Exp Med. 2018 Jul 2;215(7):1853-1868. doi: 10.1084/jem.20170779. Epub 2018 Jun 21.
• [3] Purinergic ecto-enzymes participate in the thromboregulation in acute in mice infection by Trypanosoma cruzi.Mol Cell Biochem. 2017 Aug;432(1-2):1-6. doi: 10.1007/s11010-017-2992-2. Epub 2017 Mar 11.
• [4] Anti-TIF1gamma Antibody-Positive Dermatomyositis Associated with Myelodysplastic Syndrome: Response to Treatment.Cureus. 2019 Sep 26;11(9):e5775. doi: 10.7759/cureus.5775.
• [5] Myositis-specific autoantibodies and their association with malignancy in Italian patients with polymyositis and dermatomyositis.Clin Rheumatol. 2017 Feb;36(2):469-475. doi: 10.1007/s10067-016-3453-0. Epub 2016 Oct 20.
• [6] Valproic acid inhibits epithelialmesenchymal transition in renal cell carcinoma by decreasing SMAD4 expression.Mol Med Rep. 2017 Nov;16(5):6190-6199. doi: 10.3892/mmr.2017.7394. Epub 2017 Aug 29.
• [7] Genomic analysis of head and neck squamous cell carcinoma cell lines and human tumors: a rational approach to preclinical model selection.Mol Cancer Res. 2014 Apr;12(4):571-82. doi: 10.1158/1541-7786.MCR-13-0396. Epub 2014 Jan 14.
• [8] Anti-transcriptional intermediary factor 1 gamma antibodies in cancer-associated myositis: a longitudinal study.Clin Exp Rheumatol. 2020 Jan-Feb;38(1):67-73. Epub 2019 Jul 30.
• [9] Circular RNA hsa_circ_0008305 (circPTK2) inhibits TGF--induced epithelial-mesenchymal transition and metastasis by controlling TIF1 in non-small cell lung cancer.Mol Cancer. 2018 Sep 27;17(1):140. doi: 10.1186/s12943-018-0889-7.
• [10] Inactivation of TIF1gamma cooperates with Kras to induce cystic tumors of the pancreas.PLoS Genet. 2009 Jul;5(7):e1000575. doi: 10.1371/journal.pgen.1000575. Epub 2009 Jul 24.
• [11] Up-regulation of TIF1 by valproic acid inhibits the epithelial mesenchymal transition in prostate carcinoma through TGF-/Smad signaling pathway.Eur J Pharmacol. 2019 Oct 5;860:172551. doi: 10.1016/j.ejphar.2019.172551. Epub 2019 Jul 16.
• [12] Targeting the tumor promoting effects of adenosine in chronic lymphocytic leukemia.Crit Rev Oncol Hematol. 2018 Jun;126:24-31. doi: 10.1016/j.critrevonc.2018.03.022. Epub 2018 Mar 29.
• [13] Novel TG-FGFR1 and TRIM33-NTRK1 transcript fusions in papillary thyroid carcinoma.Genes Chromosomes Cancer. 2019 Aug;58(8):558-566. doi: 10.1002/gcc.22737. Epub 2019 Feb 18.
• [14] Common genetic variants on 1p13.2 associate with risk of autism.Mol Psychiatry. 2014 Nov;19(11):1212-9. doi: 10.1038/mp.2013.146. Epub 2013 Nov 5.
• [15] Trim33 is essential for macrophage and neutrophil mobilization to developmental or inflammatory cues.J Cell Sci. 2017 Sep 1;130(17):2797-2807. doi: 10.1242/jcs.203471. Epub 2017 Jul 19.
• [16] The transcriptional cofactor TRIM33 prevents apoptosis in B lymphoblastic leukemia by deactivating a single enhancer.Elife. 2015 Apr 28;4:e06377. doi: 10.7554/eLife.06377.
• [17] Prognostic role of Tif1 expression and circulating tumor cells in patients with breast cancer.Mol Med Rep. 2019 May;19(5):3685-3695. doi: 10.3892/mmr.2019.10033. Epub 2019 Mar 14.
• [18] Transcription intermediary factor 1 is a tumor suppressor in mouse and human chronic myelomonocytic leukemia.J Clin Invest. 2011 Jun;121(6):2361-70. doi: 10.1172/JCI45213. Epub 2011 May 2.
• [19] Anti-TIF1 antibody and the expression of TIF1 in idiopathic inflammatory myopathies.Int J Rheum Dis. 2019 Feb;22(2):314-320. doi: 10.1111/1756-185X.13424. Epub 2018 Nov 5.
• [20] 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.
• [21] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [22] 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.
• [23] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [24] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [25] 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.
• [26] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [27] The transforming growth factor-beta family members bone morphogenetic protein-2 and macrophage inhibitory cytokine-1 as mediators of the antiangiogenic activity of N-(4-hydroxyphenyl)retinamide. Clin Cancer Res. 2005 Jun 15;11(12):4610-9.
• [28] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [29] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [30] 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.
• [31] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [32] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [33] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.