Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOBD7YO)

• DOT Name: T-cell activation inhibitor, mitochondrial (TCAIM)
• Synonyms: Tolerance associated gene-1 protein; TOAG-1
• Gene Name: TCAIM
• Related Disease: Psoriasis
• UniProt ID: TCAIM_HUMAN
• Pfam ID: PF14687 ; PF14688
• Sequence:
  MFCHLRPMRRLCLEKIFPHWFPFSRALSGAEAVNALRPFYFAVHPDFFGQHPVEREINEN
  SLKRLSVYLENLQKPGFKSLKPTQLTFYVRETDQSSSDGQEPFSTSGFRAVKFTLHTRDL
  LSTVLYILNSCSLSVEHIQSLNTNMHTQPLKEAKRMPDRPIKWDKSYYSFTGFKDPDEDL
  EQVSRVETTLTSWLDNNGKSAVKKLKNSLPLRKELDRLKDELSHQLQLSDIRWQRSWGIA
  HRCSQLHSLSRLAQQNLETLKKAKGCTIIFTDRSGMSAVGHVMLGTMDVHHHWTKLFERL
  PSYFDLQRRLMILEDQISYLLGGIQVVYIEELQPVLTLEEYYSLLDVFYNRLLKSRILFH
  PRSLRGLQMILNSDRYAPSLHELGHFNIPTLCDPANLQWFILTKAQQARENMKRKEELKV
  IENELIQASTKKFSLEKLYKEPSISSIQMVDCCKRLLEQSLPYLHGMHLCISHFYSVMQD
  GDLCIPWNWKNGEAIK
• Function: May regulate T-cell apoptosis.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Psoriasis	DIS59VMN	Strong	Altered Expression	[1]

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 T-cell activation inhibitor, mitochondrial (TCAIM).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of T-cell activation inhibitor, mitochondrial (TCAIM).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of T-cell activation inhibitor, mitochondrial (TCAIM).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of T-cell activation inhibitor, mitochondrial (TCAIM).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of T-cell activation inhibitor, mitochondrial (TCAIM).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of T-cell activation inhibitor, mitochondrial (TCAIM).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of T-cell activation inhibitor, mitochondrial (TCAIM).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of T-cell activation inhibitor, mitochondrial (TCAIM).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of T-cell activation inhibitor, mitochondrial (TCAIM).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of T-cell activation inhibitor, mitochondrial (TCAIM).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of T-cell activation inhibitor, mitochondrial (TCAIM).	[11]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of T-cell activation inhibitor, mitochondrial (TCAIM).	[12]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of T-cell activation inhibitor, mitochondrial (TCAIM).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of T-cell activation inhibitor, mitochondrial (TCAIM).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of T-cell activation inhibitor, mitochondrial (TCAIM).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of T-cell activation inhibitor, mitochondrial (TCAIM).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of T-cell activation inhibitor, mitochondrial (TCAIM).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of T-cell activation inhibitor, mitochondrial (TCAIM).	[19]

References

• [1] Expression of tolerance associated gene-1, a mitochondrial protein inhibiting T cell activation, can be used to predict response to immune modulating therapies.J Immunol. 2009 Sep 15;183(6):4077-87. doi: 10.4049/jimmunol.0804351. Epub 2009 Aug 14.
• [2] 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.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] 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.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [10] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [13] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] 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.
• [15] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [16] 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.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.