Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT54OKC3)

• DOT Name: mRNA export factor RAE1 (RAE1)
• Synonyms: Rae1 protein homolog; mRNA-associated protein mrnp 41
• Gene Name: RAE1
• Related Disease:
  Adult lymphoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Hepatocellular carcinoma
  Lymphoma
  Myocardial infarction
  Pediatric lymphoma
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Neoplasm
  Neuroblastoma
• UniProt ID: RAE1L_HUMAN
• PDB ID: 3MMY; 4OWR; 7F60; 7F90; 7VPG; 7VPH
• Pfam ID: PF00400
• Sequence:
  MSLFGTTSGFGTSGTSMFGSATTDNHNPMKDIEVTSSPDDSIGCLSFSPPTLPGNFLIAG
  SWANDVRCWEVQDSGQTIPKAQQMHTGPVLDVCWSDDGSKVFTASCDKTAKMWDLSSNQA
  IQIAQHDAPVKTIHWIKAPNYSCVMTGSWDKTLKFWDTRSSNPMMVLQLPERCYCADVIY
  PMAVVATAERGLIVYQLENQPSEFRRIESPLKHQHRCVAIFKDKQNKPTGFALGSIEGRV
  AIHYINPPNPAKDNFTFKCHRSNGTNTSAPQDIYAVNGIAFHPVHGTLATVGSDGRFSFW
  DKDARTKLKTSEQLDQPISACCFNHNGNIFAYASSYDWSKGHEFYNPQKKNYIFLRNAAE
  ELKPRNKK
• Function: Acts as a mRNA export factor involved in nucleocytoplasmic transport. Plays a role in mitotic bipolar spindle formation. May function in attaching cytoplasmic mRNPs to the cytoskeleton both directly or indirectly.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  Amyotrophic lateral sclerosis (hsa05014)
  Influenza A (hsa05164)
• Reactome Pathway:
  Transport of the SLBP independent Mature mRNA (R-HSA-159227)
  Transport of the SLBP Dependant Mature mRNA (R-HSA-159230)
  Transport of Mature mRNA Derived from an Intronless Transcript (R-HSA-159231)
  Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236)
  Rev-mediated nuclear export of HIV RNA (R-HSA-165054)
  Transport of Ribonucleoproteins into the Host Nucleus (R-HSA-168271)
  NS1 Mediated Effects on Host Pathways (R-HSA-168276)
  Viral Messenger RNA Synthesis (R-HSA-168325)
  NEP/NS2 Interacts with the Cellular Export Machinery (R-HSA-168333)
  Regulation of Glucokinase by Glucokinase Regulatory Protein (R-HSA-170822)
  Nuclear import of Rev protein (R-HSA-180746)
  Vpr-mediated nuclear import of PICs (R-HSA-180910)
  snRNP Assembly (R-HSA-191859)
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)
  SUMOylation of ubiquitinylation proteins (R-HSA-3232142)
  Nuclear Pore Complex (NPC) Disassembly (R-HSA-3301854)
  Regulation of HSF1-mediated heat shock response (R-HSA-3371453)
  SUMOylation of SUMOylation proteins (R-HSA-4085377)
  SUMOylation of chromatin organization proteins (R-HSA-4551638)
  SUMOylation of RNA binding proteins (R-HSA-4570464)
  SUMOylation of DNA replication proteins (R-HSA-4615885)
  Transcriptional regulation by small RNAs (R-HSA-5578749)
  Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC) (R-HSA-5619107)
  tRNA processing in the nucleus (R-HSA-6784531)
  HCMV Early Events (R-HSA-9609690)
  HCMV Late Events (R-HSA-9610379)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult lymphoma	DISK8IZR	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Lymphoma	DISN6V4S	Strong	Biomarker	[1]
Myocardial infarction	DIS655KI	Strong	Altered Expression	[5]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[1]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Biomarker	[6]
Liver cancer	DISDE4BI	moderate	Biomarker	[6]
Neoplasm	DISZKGEW	moderate	Biomarker	[7]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[8]

8 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 mRNA export factor RAE1 (RAE1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of mRNA export factor RAE1 (RAE1).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of mRNA export factor RAE1 (RAE1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of mRNA export factor RAE1 (RAE1).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of mRNA export factor RAE1 (RAE1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of mRNA export factor RAE1 (RAE1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of mRNA export factor RAE1 (RAE1).	[16]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of mRNA export factor RAE1 (RAE1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of mRNA export factor RAE1 (RAE1).	[15]

References

• [1] CBP/p300 acetyltransferases regulate the expression of NKG2D ligands on tumor cells.Oncogene. 2017 Feb 16;36(7):933-941. doi: 10.1038/onc.2016.259. Epub 2016 Aug 1.
• [2] mRNA export protein THOC5 as a tool for identification of target genes for cancer therapy.Cancer Lett. 2016 Apr 10;373(2):222-6. doi: 10.1016/j.canlet.2016.01.045. Epub 2016 Jan 28.
• [3] RAE1 mediated ZEB1 expression promotes epithelial-mesenchymal transition in breast cancer.Sci Rep. 2019 Feb 27;9(1):2977. doi: 10.1038/s41598-019-39574-8.
• [4] Depletion of three combined THOC5 mRNA export protein target genes synergistically induces human hepatocellular carcinoma cell death.Oncogene. 2016 Jul 21;35(29):3872-9. doi: 10.1038/onc.2015.433. Epub 2015 Nov 9.
• [5] Blockade of NKG2D/NKG2D ligand interaction attenuated cardiac remodelling after myocardial infarction.Cardiovasc Res. 2019 Mar 15;115(4):765-775. doi: 10.1093/cvr/cvy254.
• [6] Activation of cellular immunity and marked inhibition of liver cancer in a mouse model following gene therapy and tumor expression of GM-SCF, IL-21, and Rae-1.Mol Cancer. 2013 Dec 18;12(1):166. doi: 10.1186/1476-4598-12-166.
• [7] Induction of NKG2D Ligands on Solid Tumors Requires Tumor-Specific CD8(+) T Cells and Histone Acetyltransferases.Cancer Immunol Res. 2017 Apr;5(4):300-311. doi: 10.1158/2326-6066.CIR-16-0234. Epub 2017 Feb 21.
• [8] Retinoic acid downregulates Rae1 leading to APC(Cdh1) activation and neuroblastoma SH-SY5Y differentiation.Oncogene. 2008 May 22;27(23):3339-44. doi: 10.1038/sj.onc.1210987. Epub 2008 Jan 21.
• [9] 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.
• [10] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [13] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [16] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [17] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.