Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGNAX3H)

• DOT Name: CCAAT/enhancer-binding protein gamma (CEBPG)
• Synonyms: C/EBP gamma
• Gene Name: CEBPG
• Related Disease:
  Acute myelogenous leukaemia
  Heroin dependence
  Respiratory failure
• UniProt ID: CEBPG_HUMAN
• Pfam ID: PF07716
• Sequence:
  MSKISQQNSTPGVNGISVIHTQAHASGLQQVPQLVPAGPGGGGKAVAPSKQSKKSSPMDR
  NSDEYRQRRERNNMAVKKSRLKSKQKAQDTLQRVNQLKEENERLEAKIKLLTKELSVLKD
  LFLEHAHNLADNVQSISTENTTADGDNAGQ
• Function: Transcription factor that binds to the promoter and the enhancer regions of target genes. Binds to the enhancer element PRE-I (positive regulatory element-I) of the IL-4 gene. Binds to the promoter and the enhancer of the immunoglobulin heavy chain. Binds to GPE1, a cis-acting element in the G-CSF gene promoter.
• KEGG Pathway: Tuberculosis (hsa05152)
• Reactome Pathway:
  Response of EIF2AK4 (GCN2) to amino acid deficiency (R-HSA-9633012)
  Response of EIF2AK1 (HRI) to heme deficiency (R-HSA-9648895)
  ATF4 activates genes in response to endoplasmic reticulum stress (R-HSA-380994)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Heroin dependence	DISQ1H57	Strong	Biomarker	[2]
Respiratory failure	DISVMYJO	Limited	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[13]
Marinol	DM70IK5	Approved	Marinol decreases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[14]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[15]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[16]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[17]
Malathion	DMXZ84M	Approved	Malathion increases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[18]
Bexarotene	DMOBIKY	Approved	Bexarotene decreases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[19]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[5]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[21]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[24]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[25]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[26]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[27]
Rutin	DMEHRAJ	Investigative	Rutin decreases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[28]
CATECHIN	DMY38SB	Investigative	CATECHIN increases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[28]
AM251	DMTAWHL	Investigative	AM251 increases the expression of CCAAT/enhancer-binding protein gamma (CEBPG).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of CCAAT/enhancer-binding protein gamma (CEBPG).	[11]

References

• [1] C/EBP deregulation results in differentiation arrest in acute myeloid leukemia.J Clin Invest. 2012 Dec;122(12):4490-504. doi: 10.1172/JCI65102. Epub 2012 Nov 19.
• [2] Genetic signatures of heroin addiction.Medicine (Baltimore). 2016 Aug;95(31):e4473. doi: 10.1097/MD.0000000000004473.
• [3] C/EBP Is a Critical Regulator of Cellular Stress Response Networks through Heterodimerization with ATF4.Mol Cell Biol. 2015 Dec 14;36(5):693-713. doi: 10.1128/MCB.00911-15.
• [4] 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.
• [5] 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.
• [6] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [10] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [11] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [13] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [14] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [15] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [16] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [17] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [18] Malathion induced cancer-linked gene expression in human lymphocytes. Environ Res. 2020 Mar;182:109131. doi: 10.1016/j.envres.2020.109131. Epub 2020 Jan 10.
• [19] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] 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.
• [22] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [23] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [25] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [26] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [27] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [28] Epicatechin and a cocoa polyphenolic extract modulate gene expression in human Caco-2 cells. J Nutr. 2004 Oct;134(10):2509-16.
• [29] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.