Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGTA85X)

• DOT Name: ETS domain-containing transcription factor ERF (ERF)
• Synonyms: Ets2 repressor factor; PE-2
• Gene Name: ERF
• Related Disease:
  Craniosynostosis 4
  Chitayat syndrome
  Crouzon syndrome
  Obsolete isolated scaphocephaly
• UniProt ID: ERF_HUMAN
• PDB ID: 7JSA; 7JSL
• Pfam ID: PF00178
• Sequence:
  MKTPADTGFAFPDWAYKPESSPGSRQIQLWHFILELLRKEEYQGVIAWQGDYGEFVIKDP
  DEVARLWGVRKCKPQMNYDKLSRALRYYYNKRILHKTKGKRFTYKFNFNKLVLVNYPFID
  VGLAGGAVPQSAPPVPSGGSHFRFPPSTPSEVLSPTEDPRSPPACSSSSSSLFSAVVARR
  LGRGSVSDCSDGTSELEEPLGEDPRARPPGPPDLGAFRGPPLARLPHDPGVFRVYPRPRG
  GPEPLSPFPVSPLAGPGSLLPPQLSPALPMTPTHLAYTPSPTLSPMYPSGGGGPSGSGGG
  SHFSFSPEDMKRYLQAHTQSVYNYHLSPRAFLHYPGLVVPQPQRPDKCPLPPMAPETPPV
  PSSASSSSSSSSSPFKFKLQPPPLGRRQRAAGEKAVAGADKSGGSAGGLAEGAGALAPPP
  PPPQIKVEPISEGESEEVEVTDISDEDEEDGEVFKTPRAPPAPPKPEPGEAPGASQCMPL
  KLRFKRRWSEDCRLEGGGGPAGGFEDEGEDKKVRGEGPGEAGGPLTPRRVSSDLQHATAQ
  LSLEHRDS
• Function: Potent transcriptional repressor that binds to the H1 element of the Ets2 promoter. May regulate other genes involved in cellular proliferation. Required for extraembryonic ectoderm differentiation, ectoplacental cone cavity closure, and chorioallantoic attachment. May be important for regulating trophoblast stem cell differentiation.
• Tissue Specificity: Highest levels in testis, ovary, pancreas, and heart.
• Reactome Pathway: Oncogene Induced Senescence (R-HSA-2559585)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Craniosynostosis 4	DISZX1GK	Definitive	Autosomal dominant	[1]
Chitayat syndrome	DISLTC7H	Strong	Autosomal dominant	[2]
Crouzon syndrome	DISIAVZU	Supportive	Autosomal dominant	[3]
Obsolete isolated scaphocephaly	DISTSFJZ	Supportive	Autosomal dominant	[3]

5 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 ETS domain-containing transcription factor ERF (ERF).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of ETS domain-containing transcription factor ERF (ERF).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ETS domain-containing transcription factor ERF (ERF).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of ETS domain-containing transcription factor ERF (ERF).	[7]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of ETS domain-containing transcription factor ERF (ERF).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ETS domain-containing transcription factor ERF (ERF).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ETS domain-containing transcription factor ERF (ERF).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of ETS domain-containing transcription factor ERF (ERF).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of ETS domain-containing transcription factor ERF (ERF).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ETS domain-containing transcription factor ERF (ERF).	[11]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of ETS domain-containing transcription factor ERF (ERF).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of ETS domain-containing transcription factor ERF (ERF).	[13]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Chitayat syndrome: hyperphalangism, characteristic facies, hallux valgus and bronchomalacia results from a recurrent c.266A>G p.(Tyr89Cys) variant in the ERF gene. J Med Genet. 2017 Mar;54(3):157-165. doi: 10.1136/jmedgenet-2016-104143. Epub 2016 Oct 13.
• [3] Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis. Nat Genet. 2013 Mar;45(3):308-13. doi: 10.1038/ng.2539. Epub 2013 Jan 27.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] 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.
• [10] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [11] 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.
• [12] The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. Neurotoxicology. 2009 May;30(3):368-76.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.