Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEG9KU1)

• DOT Name: General transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1)
• Synonyms: GTF2I repeat domain-containing protein 1; General transcription factor III; MusTRD1/BEN; Muscle TFII-I repeat domain-containing protein 1; Slow-muscle-fiber enhancer-binding protein; USE B1-binding protein; Williams-Beuren syndrome chromosomal region 11 protein; Williams-Beuren syndrome chromosomal region 12 protein
• Gene Name: GTF2IRD1
• Related Disease:
  Breast neoplasm
  Depression
  Lung cancer
  Lung carcinoma
  Metastatic malignant neoplasm
  Neuromyelitis optica
  Rheumatoid arthritis
  Supravalvular aortic stenosis
  Systemic lupus erythematosus
  Thrombocytopenia
  Advanced cancer
  Colorectal carcinoma
  Differentiated thyroid carcinoma
  Neurodevelopmental disorder
  Adenocarcinoma
  Beckwith-Wiedemann syndrome
  Cognitive impairment
  Neoplasm
• UniProt ID: GT2D1_HUMAN
• PDB ID: 2D99; 2DN5; 2DZQ; 2DZR
• Pfam ID: PF02946
• Sequence:
  MALLGKRCDVPTNGCGPDRWNSAFTRKDEIITSLVSALDSMCSALSKLNAEVACVAVHDE
  SAFVVGTEKGRMFLNARKELQSDFLRFCRGPPWKDPEAEHPKKVQRGEGGGRSLPRSSLE
  HGSDVYLLRKMVEEVFDVLYSEALGRASVVPLPYERLLREPGLLAVQGLPEGLAFRRPAE
  YDPKALMAILEHSHRIRFKLKRPLEDGGRDSKALVELNGVSLIPKGSRDCGLHGQAPKVP
  PQDLPPTATSSSMASFLYSTALPNHAIRELKQEAPSCPLAPSDLGLSRPMPEPKATGAQD
  FSDCCGQKPTGPGGPLIQNVHASKRILFSIVHDKSEKWDAFIKETEDINTLRECVQILFN
  SRYAEALGLDHMVPVPYRKIACDPEAVEIVGIPDKIPFKRPCTYGVPKLKRILEERHSIH
  FIIKRMFDERIFTGNKFTKDTTKLEPASPPEDTSAEVSRATVLDLAGNARSDKGSMSEDC
  GPGTSGELGGLRPIKIEPEDLDIIQVTVPDPSPTSEEMTDSMPGHLPSEDSGYGMEMLTD
  KGLSEDARPEERPVEDSHGDVIRPLRKQVELLFNTRYAKAIGISEPVKVPYSKFLMHPEE
  LFVVGLPEGISLRRPNCFGIAKLRKILEASNSIQFVIKRPELLTEGVKEPIMDSQGTASS
  LGFSPPALPPERDSGDPLVDESLKRQGFQENYDARLSRIDIANTLREQVQDLFNKKYGEA
  LGIKYPVQVPYKRIKSNPGSVIIEGLPPGIPFRKPCTFGSQNLERILAVADKIKFTVTRP
  FQGLIPKPDEDDANRLGEKVILREQVKELFNEKYGEALGLNRPVLVPYKLIRDSPDAVEV
  TGLPDDIPFRNPNTYDIHRLEKILKAREHVRMVIINQLQPFAEICNDAKVPAKDSSIPKR
  KRKRVSEGNSVSSSSSSSSSSSSNPDSVASANQISLVQWPMYMVDYAGLNVQLPGPLNY
• Function: May be a transcription regulator involved in cell-cycle progression and skeletal muscle differentiation. May repress GTF2I transcriptional functions, by preventing its nuclear residency, or by inhibiting its transcriptional activation. May contribute to slow-twitch fiber type specificity during myogenesis and in regenerating muscles. Binds troponin I slow-muscle fiber enhancer (USE B1). Binds specifically and with high affinity to the EFG sequences derived from the early enhancer of HOXC8.
• Tissue Specificity: Highly expressed in adult skeletal muscle, heart, fibroblast, bone and fetal tissues. Expressed at lower levels in all other tissues tested.

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[1]
Depression	DIS3XJ69	Strong	Genetic Variation	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[4]
Neuromyelitis optica	DISBFGKL	Strong	Genetic Variation	[5]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[5]
Supravalvular aortic stenosis	DIS8FSJD	Strong	Biomarker	[6]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[7]
Thrombocytopenia	DISU61YW	Strong	Genetic Variation	[8]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[9]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[9]
Differentiated thyroid carcinoma	DIS1V20Y	moderate	Biomarker	[4]
Neurodevelopmental disorder	DIS372XH	moderate	Biomarker	[10]
Adenocarcinoma	DIS3IHTY	Limited	Biomarker	[11]
Beckwith-Wiedemann syndrome	DISH15GR	Limited	Biomarker	[12]
Cognitive impairment	DISH2ERD	Limited	Biomarker	[13]
Neoplasm	DISZKGEW	Limited	Altered Expression	[9]

3 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 General transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of General transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of General transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1).	[28]

15 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 General transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of General transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of General transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of General transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of General transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1).	[19]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of General transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1).	[20]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of General transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1).	[21]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of General transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1).	[22]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of General transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1).	[23]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of General transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of General transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of General transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of General transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of General transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1).	[29]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of General transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1).	[30]

References

• [1] An InVivo Gain-of-Function Screen Identifies the Williams-Beuren Syndrome Gene GTF2IRD1 as a Mammary Tumor Promoter.Cell Rep. 2016 Jun 7;15(10):2089-2096. doi: 10.1016/j.celrep.2016.05.011. Epub 2016 May 26.
• [2] A Genetic Investigation of the Well-Being Spectrum.Behav Genet. 2019 May;49(3):286-297. doi: 10.1007/s10519-019-09951-0. Epub 2019 Feb 27.
• [3] Pore-forming spider venom peptides show cytotoxicity to hyperpolarized cancer cells expressing K+ channels: A lentiviral vector approach.PLoS One. 2019 Apr 12;14(4):e0215391. doi: 10.1371/journal.pone.0215391. eCollection 2019.
• [4] Technetium-99m-pertechnetate whole-body SPET/CT scan in thyroidectomized differentiated thyroid cancer patients is a useful imaging modality in detecting remnant thyroid tissue, nodal and distant metastases before (131)I therapy. A study of 416 patients.Hell J Nucl Med. 2018 May-Aug;21(2):121-124.
• [5] Association of GTF2IRD1-GTF2I polymorphisms with neuromyelitis optica spectrum disorders in Han Chinese patients.Neural Regen Res. 2019 Feb;14(2):346-353. doi: 10.4103/1673-5374.244800.
• [6] A transcription factor involved in skeletal muscle gene expression is deleted in patients with Williams syndrome.Eur J Hum Genet. 1999 Oct-Nov;7(7):737-47. doi: 10.1038/sj.ejhg.5200396.
• [7] Association of NCF1 polymorphism with systemic lupus erythematosus and systemic sclerosis but not with ANCA-associated vasculitis in a Japanese population.Sci Rep. 2019 Nov 8;9(1):16366. doi: 10.1038/s41598-019-52920-0.
• [8] De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia.Mol Psychiatry. 2012 Feb;17(2):142-53. doi: 10.1038/mp.2011.154. Epub 2011 Nov 15.
• [9] GTF2IRD1 on chromosome 7 is a novel oncogene regulating the tumor-suppressor gene TGFR2 in colorectal cancer.Cancer Sci. 2020 Feb;111(2):343-355. doi: 10.1111/cas.14248. Epub 2019 Dec 27.
• [10] Mutation of Gtf2ird1 from the Williams-Beuren syndrome critical region results in facial dysplasia, motor dysfunction, and altered vocalisations.Neurobiol Dis. 2012 Mar;45(3):913-22. doi: 10.1016/j.nbd.2011.12.010. Epub 2011 Dec 11.
• [11] Docosahexaenoic acid induces apoptosis in lung cancer cells by increasing MKP-1 and down-regulating p-ERK1/2 and p-p38 expression.Apoptosis. 2008 Sep;13(9):1172-83. doi: 10.1007/s10495-008-0246-1.
• [12] Transaxillary robotic modified radical neck dissection: a 5-year assessment of operative and oncologic outcomes.Surg Endosc. 2017 Apr;31(4):1599-1606. doi: 10.1007/s00464-016-5146-9. Epub 2016 Aug 29.
• [13] An atypical 7q11.23 deletion in a normal IQ Williams-Beuren syndrome patient.Eur J Hum Genet. 2010 Jan;18(1):33-8. doi: 10.1038/ejhg.2009.108.
• [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] 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.
• [16] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [17] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [18] 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.
• [19] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [20] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [21] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [22] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [25] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [26] 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.
• [27] 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.
• [28] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [29] 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.
• [30] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.