Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBT0A1B)

• DOT Name: eIF5-mimic protein 1 (BZW2)
• Synonyms: Basic leucine zipper and W2 domain-containing protein 2
• Gene Name: BZW2
• Related Disease:
  Alzheimer disease
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Neoplasm
  Urinary bladder cancer
  Bone osteosarcoma
  Colorectal carcinoma
  Osteosarcoma
• UniProt ID: 5MP1_HUMAN
• Pfam ID: PF02020
• Sequence:
  MNKHQKPVLTGQRFKTRKRDEKEKFEPTVFRDTLVQGLNEAGDDLEAVAKFLDSTGSRLD
  YRRYADTLFDILVAGSMLAPGGTRIDDGDKTKMTNHCVFSANEDHETIRNYAQVFNKLIR
  RYKYLEKAFEDEMKKLLLFLKAFSETEQTKLAMLSGILLGNGTLPATILTSLFTDSLVKE
  GIAASFAVKLFKAWMAEKDANSVTSSLRKANLDKRLLELFPVNRQSVDHFAKYFTDAGLK
  ELSDFLRVQQSLGTRKELQKELQERLSQECPIKEVVLYVKEEMKRNDLPETAVIGLLWTC
  IMNAVEWNKKEELVAEQALKHLKQYAPLLAVFSSQGQSELILLQKVQEYCYDNIHFMKAF
  QKIVVLFYKADVLSEEAILKWYKEAHVAKGKSVFLDQMKKFVEWLQNAEEESESEGEEN
• Function: Translation initiation regulator which represses non-AUG initiated translation and repeat-associated non-AUG (RAN) initiated translation by acting as a competitive inhibitor of eukaryotic translation initiation factor 5 (EIF5) function. Increases the accuracy of translation initiation by impeding EIF5-dependent translation from non-AUG codons by competing with it for interaction with EIF2S2 within the 43S pre-initiation complex (PIC) in an EIF3C-binding dependent manner.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[2]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	moderate	Altered Expression	[4]
Urinary bladder cancer	DISDV4T7	moderate	Biomarker	[5]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[4]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[6]

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 eIF5-mimic protein 1 (BZW2).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of eIF5-mimic protein 1 (BZW2).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of eIF5-mimic protein 1 (BZW2).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of eIF5-mimic protein 1 (BZW2).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of eIF5-mimic protein 1 (BZW2).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of eIF5-mimic protein 1 (BZW2).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of eIF5-mimic protein 1 (BZW2).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of eIF5-mimic protein 1 (BZW2).	[13]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of eIF5-mimic protein 1 (BZW2).	[14]
Sulindac	DM2QHZU	Approved	Sulindac decreases the expression of eIF5-mimic protein 1 (BZW2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of eIF5-mimic protein 1 (BZW2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of eIF5-mimic protein 1 (BZW2).	[18]

References

• [1] Genome-wide association study of the rate of cognitive decline in Alzheimer's disease.Alzheimers Dement. 2014 Jan;10(1):45-52. doi: 10.1016/j.jalz.2013.01.008. Epub 2013 Mar 25.
• [2] Role of the novel gene BZW2 in the development of hepatocellular carcinoma.J Cell Physiol. 2019 Sep;234(9):16592-16600. doi: 10.1002/jcp.28331. Epub 2019 Feb 25.
• [3] c-Myc targeted regulators of cell metabolism in a transgenic mouse model of papillary lung adenocarcinoma.Oncotarget. 2016 Oct 4;7(40):65514-65539. doi: 10.18632/oncotarget.11804.
• [4] BZW2 promotes the malignant progression of colorectal cancer via activating the ERK/MAPK pathway.J Cell Physiol. 2020 May;235(5):4834-4842. doi: 10.1002/jcp.29361. Epub 2019 Oct 23.
• [5] BZW2 gene knockdown induces cell growth inhibition, G1 arrest and apoptosis in muscle-invasive bladder cancers: A microarray pathway analysis.J Cell Mol Med. 2019 Jun;23(6):3905-3915. doi: 10.1111/jcmm.14266. Epub 2019 Apr 1.
• [6] Downregulation of BZW2 inhibits osteosarcoma cell growth by inactivating the Akt/mTOR signaling pathway.Oncol Rep. 2017 Oct;38(4):2116-2122. doi: 10.3892/or.2017.5890. Epub 2017 Aug 8.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [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] 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.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] Growth-suppressive effect of non-steroidal anti-inflammatory drugs on 11 colon-cancer cell lines and fluorescence differential display of genes whose expression is influenced by sulindac. Int J Cancer. 2000 Dec 15;88(6):873-80. doi: 10.1002/1097-0215(20001215)88:6<873::aid-ijc6>3.0.co;2-b.
• [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] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.