Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSFG0ST)

• DOT Name: Translocating chain-associated membrane protein 2 (TRAM2)
• Gene Name: TRAM2
• Related Disease:
  Advanced cancer
  Neoplasm
  Oral cancer
  Peripheral arterial disease
• UniProt ID: TRAM2_HUMAN
• Pfam ID: PF03798
• Sequence:
  MAFRRRTKSYPLFSQEFVIHNHADIGFCLVLCVLIGLMFEVTAKTAFLFILPQYNISVPT
  ADSETVHYHYGPKDLVTILFYIFITIILHAVVQEYILDKISKRLHLSKVKHSKFNESGQL
  VVFHFTSVIWCFYVVVTEGYLTNPRSLWEDYPHVHLPFQVKFFYLCQLAYWLHALPELYF
  QKVRKEEIPRQLQYICLYLVHIAGAYLLNLSRLGLILLLLQYSTEFLFHTARLFYFADEN
  NEKLFSAWAAVFGVTRLFILTLAVLAIGFGLARMENQAFDPEKGNFNTLFCRLCVLLLVC
  AAQAWLMWRFIHSQLRHWREYWNEQSAKRRVPATPRLPARLIKRESGYHENGVVKAENGT
  SPRTKKLKSP
• Function: Necessary for collagen type I synthesis. May couple the activity of the ER Ca(2+) pump SERCA2B with the activity of the translocon. This coupling may increase the local Ca(2+) concentration at the site of collagen synthesis, and a high Ca(2+) concentration may be necessary for the function of molecular chaperones involved in collagen folding. Required for proper insertion of the first transmembrane helix N-terminus of TM4SF20 into the ER lumen, may act as a ceramide sensor for regulated alternative translocation (RAT).

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Oral cancer	DISLD42D	Strong	Altered Expression	[1]
Peripheral arterial disease	DIS78WFB	Strong	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Translocating chain-associated membrane protein 2 (TRAM2).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Translocating chain-associated membrane protein 2 (TRAM2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Translocating chain-associated membrane protein 2 (TRAM2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Translocating chain-associated membrane protein 2 (TRAM2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Translocating chain-associated membrane protein 2 (TRAM2).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Translocating chain-associated membrane protein 2 (TRAM2).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Translocating chain-associated membrane protein 2 (TRAM2).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Translocating chain-associated membrane protein 2 (TRAM2).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Translocating chain-associated membrane protein 2 (TRAM2).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Translocating chain-associated membrane protein 2 (TRAM2).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Translocating chain-associated membrane protein 2 (TRAM2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Translocating chain-associated membrane protein 2 (TRAM2).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Translocating chain-associated membrane protein 2 (TRAM2).	[15]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Translocating chain-associated membrane protein 2 (TRAM2).	[16]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Translocating chain-associated membrane protein 2 (TRAM2).	[17]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Translocating chain-associated membrane protein 2 (TRAM2).	[18]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of Translocating chain-associated membrane protein 2 (TRAM2).	[19]

References

• [1] Overexpression of Translocation Associated Membrane Protein 2 Leading to Cancer-Associated Matrix Metalloproteinase Activation as a Putative Metastatic Factor for Human Oral Cancer.J Cancer. 2018 Sep 7;9(18):3326-3333. doi: 10.7150/jca.25666. eCollection 2018.
• [2] Genetic Variants in the Bone Morphogenic Protein Gene Family Modify the Association between Residential Exposure to Traffic and Peripheral Arterial Disease.PLoS One. 2016 Apr 15;11(4):e0152670. doi: 10.1371/journal.pone.0152670. eCollection 2016.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [10] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals. Toxicology. 2013 Jan 7;303:17-24.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [17] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [18] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [19] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.