Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE1VLNB)

• DOT Name: Protein delta homolog 1 (DLK1)
• Synonyms: DLK-1; pG2
• Gene Name: DLK1
• UniProt ID: DLK1_HUMAN
• Pfam ID: PF00008
• Sequence:
  MTATEALLRVLLLLLAFGHSTYGAECFPACNPQNGFCEDDNVCRCQPGWQGPLCDQCVTS
  PGCLHGLCGEPGQCICTDGWDGELCDRDVRACSSAPCANNRTCVSLDDGLYECSCAPGYS
  GKDCQKKDGPCVINGSPCQHGGTCVDDEGRASHASCLCPPGFSGNFCEIVANSCTPNPCE
  NDGVCTDIGGDFRCRCPAGFIDKTCSRPVTNCASSPCQNGGTCLQHTQVSYECLCKPEFT
  GLTCVKKRALSPQQVTRLPSGYGLAYRLTPGVHELPVQQPEHRILKVSMKELNKKTPLLT
  EGQAICFTILGVLTSLVVLGTVGIVFLNKCETWVSNLRYNHMLRKKKNLLLQYNSGEDLA
  VNIIFPEKIDMTTFSKEAGDEEI
• Function: May have a role in neuroendocrine differentiation.
• Tissue Specificity: Found within the stromal cells in close contact to the vascular structure of placental villi, yolk sac, fetal liver, adrenal cortex and pancreas and in the beta cells of the islets of Langerhans in the adult pancreas. Found also in some forms of neuroendocrine lung tumor tissue.
• Reactome Pathway: Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Protein delta homolog 1 (DLK1) affects the response to substance of Arsenic trioxide.	[20]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	Protein delta homolog 1 (DLK1) affects the response to substance of phorbol 12-myristate 13-acetate.	[20]

4 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 Protein delta homolog 1 (DLK1).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein delta homolog 1 (DLK1).	[8]
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the methylation of Protein delta homolog 1 (DLK1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein delta homolog 1 (DLK1).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein delta homolog 1 (DLK1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein delta homolog 1 (DLK1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein delta homolog 1 (DLK1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein delta homolog 1 (DLK1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Protein delta homolog 1 (DLK1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein delta homolog 1 (DLK1).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Protein delta homolog 1 (DLK1).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Protein delta homolog 1 (DLK1).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein delta homolog 1 (DLK1).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Protein delta homolog 1 (DLK1).	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Protein delta homolog 1 (DLK1).	[13]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Protein delta homolog 1 (DLK1).	[10]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Protein delta homolog 1 (DLK1).	[14]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Protein delta homolog 1 (DLK1).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Protein delta homolog 1 (DLK1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein delta homolog 1 (DLK1).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein delta homolog 1 (DLK1).	[16]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Protein delta homolog 1 (DLK1).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein delta homolog 1 (DLK1).	[19]
BADGE	DMCK5DG	Investigative	BADGE decreases the expression of Protein delta homolog 1 (DLK1).	[14]

References

• [1] 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.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] The retinoid anticancer signal: mechanisms of target gene regulation. Br J Cancer. 2005 Aug 8;93(3):310-8. doi: 10.1038/sj.bjc.6602700.
• [4] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [7] Estrogen Regulates MAPK-Related Genes through Genomic and Nongenomic Interactions between IGF-I Receptor Tyrosine Kinase and Estrogen Receptor-Alpha Signaling Pathways in Human Uterine Leiomyoma Cells. J Signal Transduct. 2012;2012:204236. doi: 10.1155/2012/204236. Epub 2012 Oct 9.
• [8] 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.
• [9] Unique signatures of stress-induced senescent human astrocytes. Exp Neurol. 2020 Dec;334:113466. doi: 10.1016/j.expneurol.2020.113466. Epub 2020 Sep 17.
• [10] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [11] 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.
• [12] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [13] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [14] Bisphenol A diglycidyl ether induces adipogenic differentiation of multipotent stromal stem cells through a peroxisome proliferator-activated receptor gamma-independent mechanism. Environ Health Perspect. 2012 Jul;120(7):984-9. doi: 10.1289/ehp.1205063. Epub 2012 May 25.
• [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] 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.
• [17] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [18] 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.
• [19] 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.
• [20] Expression of Dlk1 gene in myelodysplastic syndrome determined by microarray, and its effects on leukemia cells. Int J Mol Med. 2008 Jul;22(1):61-8.