Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTISR7K3)

DOT Name	Neuronal migration protein doublecortin (DCX)
Synonyms	Doublin; Lissencephalin-X; Lis-X
Gene Name	DCX
Related Disease	Hepatitis C virus infection ( ) Lissencephaly spectrum disorders ( ) Lissencephaly type 1 due to doublecortin gene mutation ( ) Temporal lobe epilepsy ( ) Type-1/2 diabetes ( ) Alzheimer disease ( ) Astrocytoma ( ) Band heterotopia of brain ( ) Bladder cancer ( ) Brain neoplasm ( ) Breast cancer ( ) Breast carcinoma ( ) Ependymoma ( ) Epilepsy ( ) Hypothyroidism ( ) Intellectual disability ( ) Medulloblastoma ( ) Neoplasm ( ) Neuroblastoma ( ) Non-insulin dependent diabetes ( ) Pancreatic cancer ( ) Periventricular nodular heterotopia ( ) Schwannoma ( ) Status epilepticus seizure ( ) Stomach cancer ( ) Tuberous sclerosis ( ) Urinary bladder cancer ( ) Urinary bladder neoplasm ( ) Classic lissencephaly ( ) Glioma ( ) Intracerebral hemorrhage ( ) Prostate neoplasm ( ) Subcortical band heterotopia ( ) Adult glioblastoma ( ) Advanced cancer ( ) Amyotrophic lateral sclerosis ( ) Anxiety ( ) Anxiety disorder ( ) Glioblastoma multiforme ( ) Matthew-Wood syndrome ( ) Metastatic malignant neoplasm ( ) Nervous system inflammation ( ) Pancreatic ductal carcinoma ( ) Stroke ( )
UniProt ID	DCX_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	1MJD; 2BQQ; 2XRP; 4ATU; 5IKC; 5IN7; 5IO9; 5IOI; 5IP4; 6FNZ; 6REV; 6RF2; 6RF8; 6RFD
Pfam ID	PF03607
Sequence	MELDFGHFDERDKTSRNMRGSRMNGLPSPTHSAHCSFYRTRTLQALSNEKKAKKVRFYRN GDRYFKGIVYAVSSDRFRSFDALLADLTRSLSDNINLPQGVRYIYTIDGSRKIGSMDELE EGESYVCSSDNFFKKVEYTKNVNPNWSVNVKTSANMKAPQSLASSNSAQARENKDFVRPK LVTIIRSGVKPRKAVRVLLNKKTAHSFEQVLTDITEAIKLETGVVKKLYTLDGKQVTCLH DFFGDDDVFIACGPEKFRYAQDDFSLDENECRVMKGNPSATAGPKASPTPQKTSAKSPGP MRRSKSPADSGNDQDANGTSSSQLSTPKSKQSPISTPTSPGSLRKHKDLYLPLSLDDSDS LGDSM
Function	Microtubule-associated protein required for initial steps of neuronal dispersion and cortex lamination during cerebral cortex development. May act by competing with the putative neuronal protein kinase DCLK1 in binding to a target protein. May in that way participate in a signaling pathway that is crucial for neuronal interaction before and during migration, possibly as part of a calcium ion-dependent signal transduction pathway. May be part with PAFAH1B1/LIS-1 of overlapping, but distinct, signaling pathways that promote neuronal migration.
Tissue Specificity	Highly expressed in neuronal cells of fetal brain (in the majority of cells of the cortical plate, intermediate zone and ventricular zone), but not expressed in other fetal tissues. In the adult, highly expressed in the brain frontal lobe, but very low expression in other regions of brain, and not detected in heart, placenta, lung, liver, skeletal muscles, kidney and pancreas.
Reactome Pathway	Neurofascin interactions (R-HSA-447043 )

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Hepatitis C virus infection	DISQ0M8R	Definitive	Biomarker	[1]
Lissencephaly spectrum disorders	DISBCZL7	Definitive	X-linked	[2]
Lissencephaly type 1 due to doublecortin gene mutation	DIS9ZVA1	Definitive	X-linked	[3]
Temporal lobe epilepsy	DISNOPXX	Definitive	Biomarker	[4]
Type-1/2 diabetes	DISIUHAP	Definitive	Genetic Variation	[5]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[6]
Astrocytoma	DISL3V18	Strong	Altered Expression	[7]
Band heterotopia of brain	DISQF9HP	Strong	Biomarker	[8]
Bladder cancer	DISUHNM0	Strong	Biomarker	[9]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[7]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[10]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[10]
Ependymoma	DISUMRNZ	Strong	Biomarker	[11]
Epilepsy	DISBB28L	Strong	Biomarker	[4]
Hypothyroidism	DISR0H6D	Strong	Biomarker	[12]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[13]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[15]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[16]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[17]
Periventricular nodular heterotopia	DISU3ZRI	Strong	Genetic Variation	[18]
Schwannoma	DISTTVLA	Strong	Altered Expression	[11]
Status epilepticus seizure	DISY3BIC	Strong	Altered Expression	[19]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[20]
Tuberous sclerosis	DISEMUGZ	Strong	Biomarker	[21]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[9]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[9]
Classic lissencephaly	DISR8S3S	moderate	Biomarker	[22]
Glioma	DIS5RPEH	moderate	Biomarker	[23]
Intracerebral hemorrhage	DISC81BT	moderate	Biomarker	[24]
Prostate neoplasm	DISHDKGQ	moderate	Biomarker	[25]
Subcortical band heterotopia	DISHN7JS	Supportive	Autosomal recessive	[26]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[27]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[17]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Altered Expression	[28]
Anxiety	DISIJDBA	Limited	Biomarker	[29]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[29]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[27]
Matthew-Wood syndrome	DISA7HR7	Limited	Altered Expression	[30]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[25]
Nervous system inflammation	DISB3X5A	Limited	Altered Expression	[31]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Altered Expression	[30]
Stroke	DISX6UHX	Limited	Biomarker	[32]
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⏷ Show the Full List of 44 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Neuronal migration protein doublecortin (DCX).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Neuronal migration protein doublecortin (DCX).	[39]
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9 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Neuronal migration protein doublecortin (DCX).	[34]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Neuronal migration protein doublecortin (DCX).	[35]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Neuronal migration protein doublecortin (DCX).	[36]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Neuronal migration protein doublecortin (DCX).	[37]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Neuronal migration protein doublecortin (DCX).	[34]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Neuronal migration protein doublecortin (DCX).	[38]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Neuronal migration protein doublecortin (DCX).	[40]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Neuronal migration protein doublecortin (DCX).	[41]
Glyphosate	DM0AFY7	Investigative	Glyphosate affects the expression of Neuronal migration protein doublecortin (DCX).	[42]
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⏷ Show the Full List of 9 Drug(s)

References

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2	Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
3	Incomplete penetrance with normal MRI in a woman with germline mutation of the DCX gene. Neurology. 2001 Jul 24;57(2):327-30. doi: 10.1212/wnl.57.2.327.
4	Doublecortin-expressing cell types in temporal lobe epilepsy.Acta Neuropathol Commun. 2018 Jul 13;6(1):60. doi: 10.1186/s40478-018-0566-5.
5	Effects of long-term exposure to aluminum in the hippocampus in the type 2 diabetes model rats.Toxicol Res (Camb). 2018 Dec 3;8(2):206-215. doi: 10.1039/c8tx00192h. eCollection 2019 Mar 1.
6	Granulocyte-macrophage colony-stimulating factor neuroprotective activities in Alzheimer's disease mice.J Neuroimmunol. 2018 Jun 15;319:80-92. doi: 10.1016/j.jneuroim.2018.03.009. Epub 2018 Mar 17.
7	Doublecortin is preferentially expressed in invasive human brain tumors.Acta Neuropathol. 2005 Nov;110(5):472-80. doi: 10.1007/s00401-005-1070-0. Epub 2005 Sep 30.
8	Abnormal network activity in a targeted genetic model of human double cortex.J Neurosci. 2009 Jan 14;29(2):313-27. doi: 10.1523/JNEUROSCI.4093-08.2009.
9	DCAMKL1 is associated with the malignant status and poor outcome in bladder cancer.Tumour Biol. 2017 Jun;39(6):1010428317703822. doi: 10.1177/1010428317703822.
10	MultiDCoX: Multi-factor analysis of differential co-expression.BMC Bioinformatics. 2017 Dec 28;18(Suppl 16):576. doi: 10.1186/s12859-017-1963-7.
11	Expression of doublecortin in tumours of the central and peripheral nervous system and in human non-neuronal tissues.Acta Neuropathol. 2006 Mar;111(3):247-54. doi: 10.1007/s00401-006-0038-z. Epub 2006 Mar 7.
12	Hypothyroidism increases cyclooxygenase-2 levels and pro-inflammatory response and decreases cell proliferation and neuroblast differentiation in the hippocampus.Mol Med Rep. 2018 Apr;17(4):5782-5788. doi: 10.3892/mmr.2018.8605. Epub 2018 Feb 13.
13	Early born neurons are abnormally positioned in the doublecortin knockout hippocampus.Hum Mol Genet. 2017 Jan 1;26(1):90-108. doi: 10.1093/hmg/ddw370.
14	Enhancement of cytotoxic effects of gemcitabine by Dclk1 inhibition through suppression of Chk1 phosphorylation in human pancreatic cancer cells.Oncol Rep. 2017 Nov;38(5):3238-3244. doi: 10.3892/or.2017.5974. Epub 2017 Sep 20.
15	Highly sensitive assessment of neuroblastoma minimal residual disease in ovarian tissue using RT-qPCR-A strategy for improving the safety of fertility restoration.Pediatr Blood Cancer. 2017 May;64(5). doi: 10.1002/pbc.26287. Epub 2016 Oct 12.
16	Type 2 diabetes impairs odour detection, olfactory memory and olfactory neuroplasticity; effects partly reversed by the DPP-4 inhibitor Linagliptin.Acta Neuropathol Commun. 2018 Feb 23;6(1):14. doi: 10.1186/s40478-018-0517-1.
17	The Histone Demethylase KDM3A, Increased in Human Pancreatic Tumors, Regulates Expression of DCLK1 and Promotes Tumorigenesis in Mice.Gastroenterology. 2019 Dec;157(6):1646-1659.e11. doi: 10.1053/j.gastro.2019.08.018. Epub 2019 Aug 20.
18	Somatic mutations in cerebral cortical malformations.N Engl J Med. 2014 Aug 21;371(8):733-43. doi: 10.1056/NEJMoa1314432.
19	Disentangling chemical and electrical effects of status epilepticus-induced dentate gyrus abnormalities.Epilepsy Behav. 2021 Aug;121(Pt B):106575. doi: 10.1016/j.yebeh.2019.106575. Epub 2019 Nov 5.
20	Cyclooxygenase 2 in gastric carcinoma is expressed in doublecortin- and CaM kinase-like-1-positive tuft cells.Gut Liver. 2014 Sep;8(5):508-18. doi: 10.5009/gnl13237. Epub 2014 Apr 23.
21	Doublecortin-like (DCL) expression in focal cortical dysplasia and cortical tubers.Epilepsia. 2009 Dec;50(12):2629-37. doi: 10.1111/j.1528-1167.2009.02191.x. Epub 2009 Jul 2.
22	NuMA1 promotes axon initial segment assembly through inhibition of endocytosis.J Cell Biol. 2020 Feb 3;219(2):e201907048. doi: 10.1083/jcb.201907048.
23	Doublecortin induces mitotic microtubule catastrophe and inhibits glioma cell invasion.J Neurochem. 2009 Jan;108(1):231-45. doi: 10.1111/j.1471-4159.2008.05758.x.
24	[Neurogenesis in the dentate gyrus of the hippocampus in a rat model of intracerebral hemorrhage].Nan Fang Yi Ke Da Xue Xue Bao. 2013 Oct;33(10):1437-41.
25	Progenitors from the central nervous system drive neurogenesis in cancer.Nature. 2019 May;569(7758):672-678. doi: 10.1038/s41586-019-1219-y. Epub 2019 May 15.
26	Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
27	Ectopic doublecortin gene expression suppresses the malignant phenotype in glioblastoma cells.Cancer Res. 2006 Dec 15;66(24):11726-35. doi: 10.1158/0008-5472.CAN-06-1978.
28	The TGF- System As a Potential Pathogenic Player in Disease Modulation of Amyotrophic Lateral Sclerosis.Front Neurol. 2017 Dec 15;8:669. doi: 10.3389/fneur.2017.00669. eCollection 2017.
29	Cafeteria-diet effects on cognitive functions, anxiety, fear response and neurogenesis in the juvenile rat.Neurobiol Learn Mem. 2018 Nov;155:197-207. doi: 10.1016/j.nlm.2018.07.014. Epub 2018 Jul 31.
30	Doublecortin and CaM kinase-like-1 as an independent prognostic factor in patients with resected pancreatic carcinoma.World J Gastroenterol. 2017 Aug 21;23(31):5764-5772. doi: 10.3748/wjg.v23.i31.5764.
31	Long-term effects of autoimmune CNS inflammation on adult hippocampal neurogenesis.J Neurosci Res. 2017 Jul;95(7):1446-1458. doi: 10.1002/jnr.23982. Epub 2016 Oct 26.
32	Exosomes from miRNA-126-modified ADSCs promotes functional recovery after stroke in rats by improving neurogenesis and suppressing microglia activation.Am J Transl Res. 2019 Feb 15;11(2):780-792. eCollection 2019.
33	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.
34	Effects of all-trans and 9-cis retinoic acid on differentiating human neural stem cells in vitro. Toxicology. 2023 Mar 15;487:153461. doi: 10.1016/j.tox.2023.153461. Epub 2023 Feb 16.
35	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.
36	Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
37	Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies. Toxicol Appl Pharmacol. 2021 Dec 15;433:115792. doi: 10.1016/j.taap.2021.115792. Epub 2021 Nov 3.
38	Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
39	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.
40	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.
41	Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
42	Glyphosate-based herbicide induces long-lasting impairment in neuronal and glial differentiation. Environ Toxicol. 2022 Aug;37(8):2044-2057. doi: 10.1002/tox.23549. Epub 2022 Apr 29.