Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4F8RFH)

• DOT Name: Glucocorticoid modulatory element-binding protein 1 (GMEB1)
• Synonyms: GMEB-1; DNA-binding protein p96PIF; Parvovirus initiation factor p96; PIF p96
• Gene Name: GMEB1
• Related Disease:
  Neoplasm
  Non-small-cell lung cancer
  Neuroblastoma
• UniProt ID: GMEB1_HUMAN
• PDB ID: 1OQJ
• Pfam ID: PF01342
• Sequence:
  MANAEVSVPVGDVVVVPTEGNEGENPEDTKTQVILQLQPVQQGLFIDGHFYNRIYEAGSE
  NNTAVVAVETHTIHKIEEGIDTGTIEANEDMEIAYPITCGESKAILLWKKFVCPGINVKC
  VKFNDQLISPKHFVHLAGKSTLKDWKRAIRLGGIMLRKMMDSGQIDFYQHDKVCSNTCRS
  TKFDLLISSARAPVPGQQTSVVQTPTSADGSITQIAISEESMEEAGLEWNSALTAAVTMA
  TEEGVKKDSEEISEDTLMFWKGIADVGLMEEVVCNIQKEIEELLRGVQQRLIQAPFQVTD
  AAVLNNVAHTFGLMDTVKKVLDNRRNQVEQGEEQFLYTLTDLERQLEEQKKQGQDHRLKS
  QTVQNVVLMPVSTPKPPKRPRLQRPASTTVLSPSPPVQQPQFTVISPITITPVGQSFSMG
  NIPVATLSQGSSPVTVHTLPSGPQLFRYATVVSSAKSSSPDTVTIHPSSSLALLSSTAMQ
  DGSTLGNMTTMVSPVELVAMESGLTSAIQAVESTSEDGQTIIEIDPAPDPEAEDTEGKAV
  ILETELRTEEKVVAEMEEHQHQVHNVEIVVLED
• Function: Trans-acting factor that binds to glucocorticoid modulatory elements (GME) present in the TAT (tyrosine aminotransferase) promoter and increases sensitivity to low concentrations of glucocorticoids. Binds also to the transferrin receptor promoter. Essential auxiliary factor for the replication of parvoviruses.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[1]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Glucocorticoid modulatory element-binding protein 1 (GMEB1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Glucocorticoid modulatory element-binding protein 1 (GMEB1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Glucocorticoid modulatory element-binding protein 1 (GMEB1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glucocorticoid modulatory element-binding protein 1 (GMEB1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Glucocorticoid modulatory element-binding protein 1 (GMEB1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Glucocorticoid modulatory element-binding protein 1 (GMEB1).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Glucocorticoid modulatory element-binding protein 1 (GMEB1).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Glucocorticoid modulatory element-binding protein 1 (GMEB1).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Glucocorticoid modulatory element-binding protein 1 (GMEB1).	[11]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Glucocorticoid modulatory element-binding protein 1 (GMEB1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Glucocorticoid modulatory element-binding protein 1 (GMEB1).	[12]

References

• [1] Glucocorticoid modulatory element-binding protein 1 (GMEB1) interacts with the de-ubiquitinase USP40 to stabilize CFLAR(L) and inhibit apoptosis in human non-small cell lung cancer cells.J Exp Clin Cancer Res. 2019 May 2;38(1):181. doi: 10.1186/s13046-019-1182-3.
• [2] GMEB1, a novel endogenous caspase inhibitor, prevents hypoxia- and oxidative stress-induced neuronal apoptosis.Neurosci Lett. 2008 Jun 13;438(1):34-7. doi: 10.1016/j.neulet.2008.04.023. Epub 2008 Apr 11.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] 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.
• [13] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.