Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMV5L8H)

• DOT Name: Transforming growth factor beta regulator 1 (TBRG1)
• Synonyms: Nuclear interactor of ARF and Mdm2
• Gene Name: TBRG1
• Related Disease:
  Adenoma
  B-cell neoplasm
  Benign neoplasm
  Hemangioma
  Neoplasm
• UniProt ID: TBRG1_HUMAN
• PDB ID: 2WZO
• Pfam ID: PF05965 ; PF05964
• Sequence:
  MSLLDGLASSPRAPLQSSKARMKKLPKKSQNEKYRLKYLRLRKAAKATVFENAAICDEIA
  RLEEKFLKAKEERRYLLKKLLQLQALTEGEVQAAAPSHSSSLPLTYGVASSVGTIQGAGP
  ISGPSTGAEEPFGKKTKKEKKEKGKENNKLEVLKKTCKKKKMAGGARKLVQPIALDPSGR
  PVFPIGLGGLTVYSLGEIITDRPGFHDESAIYPVGYCSTRIYASMKCPDQKCLYTCQIKD
  GGVQPQFEIVPEDDPQNAIVSSSADACHAELLRTISTTMGKLMPNLLPAGADFFGFSHPA
  IHNLIQSCPGARKCINYQWVKFDVCKPGDGQLPEGLPENDAAMSFEAFQRQIFDEDQNDP
  LLPGSLDLPELQPAAFVSSYQPMYLTHEPLVDTHLQHLKSPSQGSPIQSSD
• Function: Acts as a growth inhibitor. Can activate p53/TP53, causes G1 arrest and collaborates with CDKN2A to restrict proliferation, but does not require either protein to inhibit DNA synthesis. Redistributes CDKN2A into the nucleoplasm. Involved in maintaining chromosomal stability.
• Tissue Specificity: Widely expressed at low levels in most tissues, with highest levels in pancreas, lung and liver. Expression is decreased in primary tumors including lung, liver, breast, pancreas and kidney carcinomas, chronic lymphocytic leukemia and diffuse large B-cell lymphoma.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Biomarker	[1]
B-cell neoplasm	DISVY326	Strong	Biomarker	[2]
Benign neoplasm	DISDUXAD	Strong	Altered Expression	[1]
Hemangioma	DISDCGAG	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]

2 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 Transforming growth factor beta regulator 1 (TBRG1).	[3]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Transforming growth factor beta regulator 1 (TBRG1).	[10]

6 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 Transforming growth factor beta regulator 1 (TBRG1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transforming growth factor beta regulator 1 (TBRG1).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Transforming growth factor beta regulator 1 (TBRG1).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transforming growth factor beta regulator 1 (TBRG1).	[7]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Transforming growth factor beta regulator 1 (TBRG1).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transforming growth factor beta regulator 1 (TBRG1).	[9]

References

• [1] NIAM-deficient mice are predisposed to the development of proliferative lesions including B-cell lymphomas.PLoS One. 2014 Nov 13;9(11):e112126. doi: 10.1371/journal.pone.0112126. eCollection 2014.
• [2] Inhibition of the miR-155 target NIAM phenocopies the growth promoting effect of miR-155 in B-cell lymphoma.Oncotarget. 2016 Jan 19;7(3):2391-400. doi: 10.18632/oncotarget.6165.
• [3] 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.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] 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.
• [6] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [7] 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.
• [8] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [9] 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.
• [10] 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.