Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8ICC4Z)

• DOT Name: Glial cell line-derived neurotrophic factor (GDNF)
• Synonyms: hGDNF; Astrocyte-derived trophic factor; ATF
• Gene Name: GDNF
• UniProt ID: GDNF_HUMAN
• PDB ID: 2V5E; 3FUB; 4UX8; 6Q2N
• Pfam ID: PF00019
• Sequence:
  MKLWDVVAVCLVLLHTASAFPLPAGKRPPEAPAEDRSLGRRRAPFALSSDSNMPEDYPDQ
  FDDVMDFIQATIKRLKRSPDKQMAVLPRRERNRQAAAANPENSRGKGRRGQRGKNRGCVL
  TAIHLNVTDLGLGYETKEELIFRYCSGSCDAAETTYDKILKNLSRNRRLVSDKVGQACCR
  PIAFDDDLSFLDDNLVYHILRKHSAKRCGCI
• Function: Neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake.
• Tissue Specificity: In the brain, predominantly expressed in the striatum with highest levels in the caudate and lowest in the putamen. Isoform 2 is absent from most tissues except for low levels in intestine and kidney. Highest expression of isoform 3 is found in pancreatic islets. Isoform 5 is expressed at very low levels in putamen, nucleus accumbens, prefrontal cortex, amygdala, hypothalamus and intestine. Isoform 3 is up-regulated in the middle temporal gyrus of Alzheimer disease patients while isoform 2 shows no change.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Calcium sig.ling pathway (hsa04020)
  PI3K-Akt sig.ling pathway (hsa04151)
• Reactome Pathway:
  RAF/MAP kinase cascade (R-HSA-5673001)
  RET signaling (R-HSA-8853659)
  NCAM1 interactions (R-HSA-419037)

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
DTI-015	DMXZRW0	Approved	Glial cell line-derived neurotrophic factor (GDNF) decreases the response to substance of DTI-015.	[9]
Dextroamphetamine	DMMIHVP	Approved	Glial cell line-derived neurotrophic factor (GDNF) affects the response to substance of Dextroamphetamine.	[10]

3 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the secretion of Glial cell line-derived neurotrophic factor (GDNF).	[1]
Adenosine	DMM2NSK	Approved	Adenosine increases the secretion of Glial cell line-derived neurotrophic factor (GDNF).	[5]
Cordycepin	DM72Y01	Investigative	Cordycepin increases the secretion of Glial cell line-derived neurotrophic factor (GDNF).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Glial cell line-derived neurotrophic factor (GDNF).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Glial cell line-derived neurotrophic factor (GDNF).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Glial cell line-derived neurotrophic factor (GDNF).	[4]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Glial cell line-derived neurotrophic factor (GDNF).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Glial cell line-derived neurotrophic factor (GDNF).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Glial cell line-derived neurotrophic factor (GDNF).	[7]

References

• [1] An autocrine loop involving ret and glial cell-derived neurotrophic factor mediates retinoic acid-induced neuroblastoma cell differentiation. Mol Cancer Res. 2006 Jul;4(7):481-8. doi: 10.1158/1541-7786.MCR-06-0050.
• [2] 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.
• [3] Systematic transcriptome-based comparison of cellular adaptive stress response activation networks in hepatic stem cell-derived progeny and primary human hepatocytes. Toxicol In Vitro. 2021 Jun;73:105107. doi: 10.1016/j.tiv.2021.105107. Epub 2021 Feb 3.
• [4] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [5] Adenosine and Cordycepin Accelerate Tissue Remodeling Process through Adenosine Receptor Mediated Wnt/-Catenin Pathway Stimulation by Regulating GSK3b Activity. Int J Mol Sci. 2021 May 25;22(11):5571. doi: 10.3390/ijms22115571.
• [6] 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.
• [7] Bisphenol A Represses Dopaminergic Neuron Differentiation from Human Embryonic Stem Cells through Downregulating the Expression of Insulin-like Growth Factor 1. Mol Neurobiol. 2017 Jul;54(5):3798-3812. doi: 10.1007/s12035-016-9898-y. Epub 2016 Jun 7.
• [8] Effects of PQ's cytotoxicity on secretory vesicles in astroglia: Expression alternation of secretogranin II and its potential interaction with intracellular factors. Biochem Biophys Res Commun. 2018 Mar 4;497(2):675-682. doi: 10.1016/j.bbrc.2018.02.130. Epub 2018 Feb 16.
• [9] Glial cell-line derived neurotrophic factor (GDNF) family of ligands confer chemoresistance in a ligand-specific fashion in malignant gliomas. J Clin Neurosci. 2009 Mar;16(3):427-36. doi: 10.1016/j.jocn.2008.06.002. Epub 2009 Jan 12.
• [10] Behavioral improvement and dopamine release in a Parkinsonian rat model. Neurosci Lett. 2002 Sep 13;330(1):5-8. doi: 10.1016/s0304-3940(02)00672-9.