General Information of Drug Off-Target (DOT) (ID: OT3YH6J6)

DOT Name ELAV-like protein 4 (ELAVL4)
Synonyms Hu-antigen D; HuD; Paraneoplastic encephalomyelitis antigen HuD
Gene Name ELAVL4
Related Disease
Alzheimer disease ( )
Autoimmune disease ( )
Hypothyroidism ( )
Late-onset Parkinson disease ( )
Lung neoplasm ( )
Major depressive disorder ( )
Neoplasm ( )
Neuroblastoma ( )
Parkinson disease ( )
Schizophrenia ( )
Sciatic neuropathy ( )
Spinal muscular atrophy ( )
Meningioma ( )
Amyotrophic lateral sclerosis ( )
Status epilepticus seizure ( )
UniProt ID
ELAV4_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
1FXL; 1G2E
Pfam ID
PF00076
Sequence
MEWNGLKMIISTMEPQVSNGPTSNTSNGPSSNNRNCPSPMQTGATTDDSKTNLIVNYLPQ
NMTQEEFRSLFGSIGEIESCKLVRDKITGQSLGYGFVNYIDPKDAEKAINTLNGLRLQTK
TIKVSYARPSSASIRDANLYVSGLPKTMTQKELEQLFSQYGRIITSRILVDQVTGVSRGV
GFIRFDKRIEAEEAIKGLNGQKPSGATEPITVKFANNPSQKSSQALLSQLYQSPNRRYPG
PLHHQAQRFRLDNLLNMAYGVKRLMSGPVPPSACPPRFSPITIDGMTSLVGMNIPGHTGT
GWCIFVYNLSPDSDESVLWQLFGPFGAVNNVKVIRDFNTNKCKGFGFVTMTNYDEAAMAI
ASLNGYRLGDRVLQVSFKTNKAHKS
Function
RNA-binding protein that is involved in the post-transcriptional regulation of mRNAs. Plays a role in the regulation of mRNA stability, alternative splicing and translation. Binds to AU-rich element (ARE) sequences in the 3' untranslated region (UTR) of target mRNAs, including GAP43, VEGF, FOS, CDKN1A and ACHE mRNA. Many of the target mRNAs are coding for RNA-binding proteins, transcription factors and proteins involved in RNA processing and/or neuronal development and function. By binding to the mRNA 3'UTR, decreases mRNA deadenylation and thereby contributes to the stabilization of mRNA molecules and their protection from decay. Also binds to the polyadenylated (poly(A)) tail in the 3'UTR of mRNA, thereby increasing its affinity for mRNA binding. Mainly plays a role in neuron-specific RNA processing by stabilization of mRNAs such as GAP43, ACHE and mRNAs of other neuronal proteins, thereby contributing to the differentiation of neural progenitor cells, nervous system development, learning and memory mechanisms. Involved in the negative regulation of the proliferative activity of neuronal stem cells and in the positive regulation of neuronal differentiation of neural progenitor cells. Promotes neuronal differentiation of neural stem/progenitor cells in the adult subventricular zone of the hippocampus by binding to and stabilizing SATB1 mRNA. Binds and stabilizes MSI1 mRNA in neural stem cells. Exhibits increased binding to ACHE mRNA during neuronal differentiation, thereby stabilizing ACHE mRNA and enhancing its expression. Protects CDKN1A mRNA from decay by binding to its 3'-UTR. May bind to APP and BACE1 mRNAS and the BACE1AS lncRNA and enhance their stabilization. Plays a role in neurite outgrowth and in the establishment and maturation of dendritic arbors, thereby contributing to neocortical and hippocampal circuitry function. Stabilizes GAP43 mRNA and protects it from decay during postembryonic development in the brain. By promoting the stabilization of GAP43 mRNA, plays a role in NGF-mediated neurite outgrowth. Binds to BDNF long 3'UTR mRNA, thereby leading to its stabilization and increased dendritic translation after activation of PKC. By increasing translation of BDNF after nerve injury, may contribute to nerve regeneration. Acts as a stabilizing factor by binding to the 3'UTR of NOVA1 mRNA, thereby increasing its translation and enhancing its functional activity in neuron-specific splicing. Stimulates translation of mRNA in a poly(A)- and cap-dependent manner, possibly by associating with the EIF4F cap-binding complex. May also negatively regulate translation by binding to the 5'UTR of Ins2 mRNA, thereby repressing its translation. Upon glucose stimulation, Ins2 mRNA is released from ELAVL4 and translational inhibition is abolished. Also plays a role in the regulation of alternative splicing. May regulate alternative splicing of CALCA pre-mRNA into Calcitonin and Calcitonin gene-related peptide 1 (CGRP) by competing with splicing regulator TIAR for binding to U-rich intronic sequences of CALCA pre-mRNA.
Tissue Specificity Expressed in pancreatic beta cells (at protein level) . Expressed in the brain .

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Alzheimer disease DISF8S70 Strong Biomarker [1]
Autoimmune disease DISORMTM Strong Biomarker [2]
Hypothyroidism DISR0H6D Strong Biomarker [3]
Late-onset Parkinson disease DIS9IOUI Strong Genetic Variation [4]
Lung neoplasm DISVARNB Strong Genetic Variation [5]
Major depressive disorder DIS4CL3X Strong Genetic Variation [6]
Neoplasm DISZKGEW Strong Biomarker [2]
Neuroblastoma DISVZBI4 Strong Altered Expression [7]
Parkinson disease DISQVHKL Strong Biomarker [8]
Schizophrenia DISSRV2N Strong Genetic Variation [9]
Sciatic neuropathy DISMGDKX Strong Biomarker [10]
Spinal muscular atrophy DISTLKOB Strong Biomarker [11]
Meningioma DISPT4TG moderate Biomarker [12]
Amyotrophic lateral sclerosis DISF7HVM Limited Biomarker [13]
Status epilepticus seizure DISY3BIC Limited Biomarker [14]
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⏷ Show the Full List of 15 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
This DOT Affected the Drug Response of 1 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Mitoxantrone DMM39BF Approved ELAV-like protein 4 (ELAVL4) affects the response to substance of Mitoxantrone. [18]
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2 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 ELAV-like protein 4 (ELAVL4). [15]
Tretinoin DM49DUI Approved Tretinoin increases the expression of ELAV-like protein 4 (ELAVL4). [16]
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1 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 ELAV-like protein 4 (ELAVL4). [17]
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References

1 HuD regulates coding and noncoding RNA to induce APPA processing.Cell Rep. 2014 Jun 12;7(5):1401-1409. doi: 10.1016/j.celrep.2014.04.050. Epub 2014 May 22.
2 Isoaspartylation appears to trigger small cell lung cancer-associated autoimmunity against neuronal protein ELAVL4.J Neuroimmunol. 2016 Oct 15;299:70-78. doi: 10.1016/j.jneuroim.2016.09.002. Epub 2016 Sep 3.
3 Neuronal HuD gene encoding a mRNA stability regulator is transcriptionally repressed by thyroid hormone.J Neurochem. 2003 Aug;86(3):763-73. doi: 10.1046/j.1471-4159.2003.01877.x.
4 ELAVL4, PARK10, and the Celts.Mov Disord. 2007 Mar 15;22(4):585-7. doi: 10.1002/mds.21336.
5 Molecular analysis of the HuD gene in neuroendocrine lung cancers.Lung Cancer. 2010 Jan;67(1):69-75. doi: 10.1016/j.lungcan.2009.03.022.
6 Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.Nat Neurosci. 2019 Mar;22(3):343-352. doi: 10.1038/s41593-018-0326-7. Epub 2019 Feb 4.
7 Application of Serum ELAVL4 (HuD) Antigen Assay for Small Cell Lung Cancer Diagnosis.Anticancer Res. 2017 Aug;37(8):4515-4522. doi: 10.21873/anticanres.11848.
8 Association mapping of the PARK10 region for Parkinson's disease susceptibility genes.Parkinsonism Relat Disord. 2014 Jan;20(1):93-8. doi: 10.1016/j.parkreldis.2013.10.001. Epub 2013 Oct 11.
9 Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
10 Increased expression and localization of the RNA-binding protein HuD and GAP-43 mRNA to cytoplasmic granules in DRG neurons during nerve regeneration.Exp Neurol. 2003 Sep;183(1):100-8. doi: 10.1016/s0014-4886(03)00103-1.
11 Advances in understanding the role of disease-associated proteins in spinal muscular atrophy.Expert Rev Proteomics. 2017 Jul;14(7):581-592. doi: 10.1080/14789450.2017.1345631. Epub 2017 Jun 30.
12 Reduced expression of ELAVL4 in male meningioma patients.Brain Tumor Pathol. 2013 Jul;30(3):160-6. doi: 10.1007/s10014-012-0117-x. Epub 2012 Sep 11.
13 Mutant FUS and ELAVL4 (HuD) Aberrant Crosstalk in Amyotrophic Lateral Sclerosis.Cell Rep. 2019 Jun 25;27(13):3818-3831.e5. doi: 10.1016/j.celrep.2019.05.085.
14 Coordinated expression of HuD and GAP-43 in hippocampal dentate granule cells during developmental and adult plasticity.Neurochem Res. 2007 Dec;32(12):2142-51. doi: 10.1007/s11064-007-9388-8. Epub 2007 Jun 19.
15 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
16 Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
17 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.
18 Prediction of doxorubicin sensitivity in breast tumors based on gene expression profiles of drug-resistant cell lines correlates with patient survival. Oncogene. 2005 Nov 17;24(51):7542-51. doi: 10.1038/sj.onc.1208908.