Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE47B57)

• DOT Name: Protein lifeguard 3 (TMBIM1)
• Synonyms: Protein RECS1 homolog; Transmembrane BAX inhibitor motif-containing protein 1
• Gene Name: TMBIM1
• Related Disease:
  Cardiac failure
  Cardiovascular disease
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Congestive heart failure
  Fatty liver disease
  Inflammatory bowel disease
  Neoplasm
  Non-alcoholic fatty liver disease
  Crohn disease
  Ulcerative colitis
  Cardiomyopathy
• UniProt ID: LFG3_HUMAN
• Pfam ID: PF01027
• Sequence:
  MSNPSAPPPYEDRNPLYPGPPPPGGYGQPSVLPGGYPAYPGYPQPGYGHPAGYPQPMPPT
  HPMPMNYGPGHGYDGEERAVSDSFGPGEWDDRKVRHTFIRKVYSIISVQLLITVAIIAIF
  TFVEPVSAFVRRNVAVYYVSYAVFVVTYLILACCQGPRRRFPWNIILLTLFTFAMGFMTG
  TISSMYQTKAVIIAMIITAVVSISVTIFCFQTKVDFTSCTGLFCVLGIVLLVTGIVTSIV
  LYFQYVYWLHMLYAALGAICFTLFLAYDTQLVLGNRKHTISPEDYITGALQIYTDIIYIF
  TFVLQLMGDRN
• Function: Negatively regulates aortic matrix metalloproteinase-9 (MMP9) production and may play a protective role in vascular remodeling.
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac failure	DISDC067	Strong	Altered Expression	[1]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[2]
Colon cancer	DISVC52G	Strong	Genetic Variation	[3]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[3]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[3]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[3]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[3]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[4]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[3]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[1]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[5]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[5]
Crohn disease	DIS2C5Q8	moderate	Genetic Variation	[7]
Ulcerative colitis	DIS8K27O	moderate	Genetic Variation	[7]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[8]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Protein lifeguard 3 (TMBIM1) decreases the response to substance of Arsenic trioxide.	[24]

15 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 3 (TMBIM1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein lifeguard 3 (TMBIM1).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein lifeguard 3 (TMBIM1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein lifeguard 3 (TMBIM1).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein lifeguard 3 (TMBIM1).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein lifeguard 3 (TMBIM1).	[14]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Protein lifeguard 3 (TMBIM1).	[15]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Protein lifeguard 3 (TMBIM1).	[16]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Protein lifeguard 3 (TMBIM1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein lifeguard 3 (TMBIM1).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein lifeguard 3 (TMBIM1).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protein lifeguard 3 (TMBIM1).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Protein lifeguard 3 (TMBIM1).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Protein lifeguard 3 (TMBIM1).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Protein lifeguard 3 (TMBIM1).	[23]

References

• [1] Targeting Transmembrane BAX Inhibitor Motif Containing 1 Alleviates Pathological Cardiac Hypertrophy.Circulation. 2018 Apr 3;137(14):1486-1504. doi: 10.1161/CIRCULATIONAHA.117.031659. Epub 2017 Dec 11.
• [2] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [3] Novel Common Genetic Susceptibility Loci for Colorectal Cancer.J Natl Cancer Inst. 2019 Feb 1;111(2):146-157. doi: 10.1093/jnci/djy099.
• [4] Genetic variant of TMBIM1 is associated with the susceptibility of colorectal cancer in the Chinese population.Clin Res Hepatol Gastroenterol. 2019 Jun;43(3):324-329. doi: 10.1016/j.clinre.2018.10.013. Epub 2018 Nov 15.
• [5] Tmbim1 is a multivesicular body regulator that protects against non-alcoholic fatty liver disease in mice and monkeys by targeting the lysosomal degradation of Tlr4.Nat Med. 2017 Jun;23(6):742-752. doi: 10.1038/nm.4334. Epub 2017 May 8.
• [6] Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
• [7] Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.Nat Genet. 2015 Sep;47(9):979-986. doi: 10.1038/ng.3359. Epub 2015 Jul 20.
• [8] Up regulated Tmbim1 activation promotes high fat diet (HFD)-induced cardiomyopathy by enhancement of inflammation and oxidative stress.Biochem Biophys Res Commun. 2018 Oct 12;504(4):797-804. doi: 10.1016/j.bbrc.2018.08.059. Epub 2018 Sep 11.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [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] 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.
• [14] 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.
• [15] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [16] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [17] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [18] 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.
• [19] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [24] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.