Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8712PP)

• DOT Name: Protein lifeguard 4 (TMBIM4)
• Synonyms: Golgi anti-apoptotic protein; Protein S1R; Transmembrane BAX inhibitor motif-containing protein 4; Z-protein
• Gene Name: TMBIM4
• Related Disease:
  Alpha-1 antitrypsin deficiency
  Lassa fever
  Lassa virus infectious disease
  Non-insulin dependent diabetes
  Viral hemorrhagic fever
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Advanced cancer
  Nasopharyngeal carcinoma
  Venous thromboembolism
• UniProt ID: LFG4_HUMAN
• Pfam ID: PF01027
• Sequence:
  MADPDPRYPRSSIEDDFNYGSSVASATVHIRMAFLRKVYSILSLQVLLTTVTSTVFLYFE
  SVRTFVHESPALILLFALGSLGLIFALILNRHKYPLNLYLLFGFTLLEALTVAVVVTFYD
  VYIILQAFILTTTVFFGLTVYTLQSKKDFSKFGAGLFALLWILCLSGFLKFFFYSEIMEL
  VLAAAGALLFCGFIIYDTHSLMHKLSPEEYVLAAISLYLDIINLFLHLLRFLEAVNKK
• Function: Anti-apoptotic protein which can inhibit apoptosis induced by intrinsic and extrinsic apoptotic stimuli. Can modulate both capacitative Ca2+ entry and inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ release.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alpha-1 antitrypsin deficiency	DISQKEHW	Strong	Genetic Variation	[1]
Lassa fever	DISKFYGZ	Strong	Biomarker	[2]
Lassa virus infectious disease	DISHZ5WC	Strong	Biomarker	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[3]
Viral hemorrhagic fever	DISQEBTU	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	moderate	Altered Expression	[5]
Prostate cancer	DISF190Y	moderate	Biomarker	[5]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[5]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[6]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[7]
Venous thromboembolism	DISUR7CR	Limited	Genetic Variation	[8]

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 Protein lifeguard 4 (TMBIM4).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein lifeguard 4 (TMBIM4).	[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 Protein lifeguard 4 (TMBIM4).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein lifeguard 4 (TMBIM4).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein lifeguard 4 (TMBIM4).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein lifeguard 4 (TMBIM4).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein lifeguard 4 (TMBIM4).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein lifeguard 4 (TMBIM4).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein lifeguard 4 (TMBIM4).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Protein lifeguard 4 (TMBIM4).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein lifeguard 4 (TMBIM4).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein lifeguard 4 (TMBIM4).	[20]

References

• [1] Semiquantitation of Monomer and Polymer Alpha-1 Antitrypsin by Centrifugal Separation and Assay by Western Blot of Soluble and Insoluble Components.Methods Mol Biol. 2017;1639:227-234. doi: 10.1007/978-1-4939-7163-3_23.
• [2] Antibodies to Lassa virus Z protein and nucleoprotein co-occur in human sera from Lassa fever endemic regions.Med Microbiol Immunol. 2001 Sep;189(4):225-9. doi: 10.1007/s004300100061.
• [3] T-cadherin gene variants are associated with type 2 diabetes and the Fatty Liver Index in the French population.Diabetes Metab. 2017 Feb;43(1):33-39. doi: 10.1016/j.diabet.2016.05.005. Epub 2016 Jun 8.
• [4] A Highly Conserved Leucine in Mammarenavirus Matrix Z Protein Is Required for Z Interaction with the Virus L Polymerase and Z Stability in Cells Harboring an Active Viral Ribonucleoprotein.J Virol. 2018 May 14;92(11):e02256-17. doi: 10.1128/JVI.02256-17. Print 2018 Jun 1.
• [5] Histone H2A.Z prepares the prostate specific antigen (PSA) gene for androgen receptor-mediated transcription and is upregulated in a model of prostate cancer progression.Cancer Lett. 2012 Feb 1;315(1):38-47. doi: 10.1016/j.canlet.2011.10.003. Epub 2011 Oct 12.
• [6] Golgi anti-apoptotic protein: a tale of camels, calcium, channels and cancer.Open Biol. 2017 May;7(5):170045. doi: 10.1098/rsob.170045.
• [7] Matrix metalloproteinase 9 is induced by the Epstein-Barr virus BZLF1 transactivator.Clin Exp Metastasis. 1999 Jul;17(5):431-6. doi: 10.1023/a:1006699003525.
• [8] Polymorphisms of the Z protein protease inhibitor and risk of venous thromboembolism: a meta-analysis.Br J Haematol. 2008 Oct;143(2):284-7. doi: 10.1111/j.1365-2141.2008.07331.x. Epub 2008 Aug 15.
• [9] 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.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [12] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [16] 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.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] 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.
• [20] Genome-wide gene expression profiling of low-dose, long-term exposure of human osteosarcoma cells to bisphenol A and its analogs bisphenols AF and S. Toxicol In Vitro. 2015 Aug;29(5):1060-9.