Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDPUE6Y)

• DOT Name: E2F-associated phosphoprotein (EAPP)
• Synonyms: EAPP
• Gene Name: EAPP
• Related Disease: Holoprosencephaly
• UniProt ID: EAPP_HUMAN
• Pfam ID: PF10238
• Sequence:
  MNRLPDDYDPYAVEEPSDEEPALSSSEDEVDVLLHGTPDQKRKLIRECLTGESESSSEDE
  FEKEMEAELNSTMKTMEDKLSSLGTGSSSGNGKVATAPTRYYDDIYFDSDSEDEDRAVQV
  TKKKKKKQHKIPTNDELLYDPEKDNRDQAWVDAQRRGYHGLGPQRSRQQQPVPNSDAVLN
  CPACMTTLCLDCQRHESYKTQYRAMFVMNCSINKEEVLRYKASENRKKRRVHKKMRSNRE
  DAAEKAETDVEEIYHPVMCTECSTEVAVYDKDEVFHFFNVLASHS
• Function: May play an important role in the fine-tuning of both major E2F1 activities, the regulation of the cell-cycle and the induction of apoptosis. Promotes S-phase entry, and inhibits p14(ARP) expression.
• Tissue Specificity: Ubiquitously expressed. Highest levels in heart, placenta, skeletal muscle and pancreas. Lower levels in brain, lung and kidney. In the brain, expressed in all regions with high levels in the cerebellum and cerebral cortex. Expressed in COS1 and transformed skin fibroblasts.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Holoprosencephaly	DISR35EC	Definitive	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E2F-associated phosphoprotein (EAPP).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E2F-associated phosphoprotein (EAPP).	[3]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of E2F-associated phosphoprotein (EAPP).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the phosphorylation of E2F-associated phosphoprotein (EAPP).	[4]
G1	DMTV42K	Phase 1/2	G1 decreases the phosphorylation of E2F-associated phosphoprotein (EAPP).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E2F-associated phosphoprotein (EAPP).	[5]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of E2F-associated phosphoprotein (EAPP).	[6]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of E2F-associated phosphoprotein (EAPP).	[8]

References

• [1] Defining a holoprosencephaly locus on human chromosome 14q13 and characterization of potential candidate genes.Genomics. 2005 May;85(5):608-21. doi: 10.1016/j.ygeno.2005.01.010.
• [2] 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.
• [3] 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.
• [4] The G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Nuclear Estrogen Receptor Activity and Stimulates Novel Phosphoproteomic Signatures. Toxicol Sci. 2016 Jun;151(2):434-46. doi: 10.1093/toxsci/kfw057. Epub 2016 Mar 29.
• [5] 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.
• [6] 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.
• [7] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [8] 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.