Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3I0H8E)

• DOT Name: Translocating chain-associated membrane protein 1 (TRAM1)
• Synonyms: Protein TRAM1
• Gene Name: TRAM1
• Related Disease:
  Lung cancer
  Respiratory syncytial virus infection
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Clear cell renal carcinoma
  Colorectal carcinoma
  Corneal neovascularization
  Endometrial cancer
  Endometrial carcinoma
  Glioma
  Hepatocellular carcinoma
  High blood pressure
  Hypothyroidism
  Influenza
  Neuralgia
  Prostate adenocarcinoma
  Pulmonary arterial hypertension
  Pulmonary fibrosis
  Renal cell carcinoma
  Renal fibrosis
  Carcinoma
  Neuroendocrine cancer
  Obesity
  Metastatic malignant neoplasm
  Adult glioblastoma
  Advanced cancer
  Castration-resistant prostate carcinoma
  Glioblastoma multiforme
  Non-insulin dependent diabetes
  Parkinson disease
  Prostate neoplasm
  Type-1/2 diabetes
• UniProt ID: TRAM1_HUMAN
• Pfam ID: PF03798
• Sequence:
  MAIRKKSTKSPPVLSHEFVLQNHADIVSCVAMVFLLGLMFEITAKASIIFVTLQYNVTLP
  ATEEQATESVSLYYYGIKDLATVFFYMLVAIIIHAVIQEYMLDKINRRMHFSKTKHSKFN
  ESGQLSAFYLFACVWGTFILISENYISDPTILWRAYPHNLMTFQMKFFYISQLAYWLHAF
  PELYFQKTKKEDIPRQLVYIGLYLFHIAGAYLLNLNHLGLVLLVLHYFVEFLFHISRLFY
  FSNEKYQKGFSLWAVLFVLGRLLTLILSVLTVGFGLARAENQKLDFSTGNFNVLAVRIAV
  LASICVTQAFMMWKFINFQLRRWREHSAFQAPAVKKKPTVTKGRSSKKGTENGVNGTLTS
  NVADSPRNKKEKSS
• Function: Involved in the translocation of nascent protein chains into or through the endoplasmic reticulum (ER) membrane by facilitating the proper chain positioning at the SEC61 channel. Regulates the exposure of nascent secretory protein chain to the cytosol during translocation into the ER. May affect the phospholipid bilayer in the vicinity of the lateral gate of the SEC61 channel, thereby facilitating ER protein transport. Intimately associates with transmembrane (TM) domain of nascent membrane proteins during the entire integration process into the ER membrane. Associates with the second TM domain of G-protein-coupled receptor opsin/OPSD nascent chain in the ER membrane, which may facilitate its integration into the membrane. Under conditions of ER stress, participates in the disposal of misfolded ER membrane proteins during the unfolded protein response (UPR), an integrated stress response (ISR) pathway, by selectively retrotranslocating misfolded ER-membrane proteins from the ER into the cytosol where they are ubiquitinated and degraded by the proteasome ; (Microbial infection) In case of cytomegalovirus infection, participates in US2- and US11-mediated ER-to-cytosol retrotranslocation and subsequent degradation of major histocompatibility complex (MHC) class I heavy chains, thereby decreasing the immune detection by cytotoxic T-cells.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway: SRP-dependent cotranslational protein targeting to membrane (R-HSA-1799339)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung cancer	DISCM4YA	Definitive	Biomarker	[1]
Respiratory syncytial virus infection	DIS7FWHY	Definitive	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[4]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[4]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[6]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Corneal neovascularization	DISKOGZP	Strong	Biomarker	[9]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[10]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[10]
Glioma	DIS5RPEH	Strong	Altered Expression	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[12]
High blood pressure	DISY2OHH	Strong	Altered Expression	[13]
Hypothyroidism	DISR0H6D	Strong	Biomarker	[14]
Influenza	DIS3PNU3	Strong	Biomarker	[4]
Neuralgia	DISWO58J	Strong	Biomarker	[15]
Prostate adenocarcinoma	DISBZYU8	Strong	Biomarker	[16]
Pulmonary arterial hypertension	DISP8ZX5	Strong	Biomarker	[13]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[17]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[7]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[18]
Carcinoma	DISH9F1N	moderate	Biomarker	[19]
Neuroendocrine cancer	DISVGJET	moderate	Biomarker	[20]
Obesity	DIS47Y1K	moderate	Genetic Variation	[21]
Metastatic malignant neoplasm	DIS86UK6	Disputed	Biomarker	[22]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[23]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[24]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Genetic Variation	[25]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[23]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[26]
Parkinson disease	DISQVHKL	Limited	Biomarker	[27]
Prostate neoplasm	DISHDKGQ	Limited	Altered Expression	[28]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[29]

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 Translocating chain-associated membrane protein 1 (TRAM1).	[30]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Translocating chain-associated membrane protein 1 (TRAM1).	[42]

13 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 Translocating chain-associated membrane protein 1 (TRAM1).	[31]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Translocating chain-associated membrane protein 1 (TRAM1).	[32]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Translocating chain-associated membrane protein 1 (TRAM1).	[33]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Translocating chain-associated membrane protein 1 (TRAM1).	[34]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Translocating chain-associated membrane protein 1 (TRAM1).	[35]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Translocating chain-associated membrane protein 1 (TRAM1).	[36]
Bicalutamide	DMZMSPF	Approved	Bicalutamide increases the expression of Translocating chain-associated membrane protein 1 (TRAM1).	[37]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Translocating chain-associated membrane protein 1 (TRAM1).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Translocating chain-associated membrane protein 1 (TRAM1).	[39]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Translocating chain-associated membrane protein 1 (TRAM1).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Translocating chain-associated membrane protein 1 (TRAM1).	[41]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Translocating chain-associated membrane protein 1 (TRAM1).	[43]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Translocating chain-associated membrane protein 1 (TRAM1).	[44]

References

• [1] SRC-3 inhibition blocks tumor growth of pancreatic ductal adenocarcinoma.Cancer Lett. 2019 Feb 1;442:310-319. doi: 10.1016/j.canlet.2018.11.012. Epub 2018 Nov 10.
• [2] Respiratory syncytial virus infection modulates interleukin? production in respiratory epithelial cells through a transcription factoractivator protein? signaling pathway.Mol Med Rep. 2014 Sep;10(3):1443-7. doi: 10.3892/mmr.2014.2357. Epub 2014 Jun 26.
• [3] KCa3.1 Channel Modulators as Potential Therapeutic Compounds for Glioblastoma.Curr Neuropharmacol. 2018;16(5):618-626. doi: 10.2174/1570159X15666170630164226.
• [4] The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to atherogenesis in mice and humans.J Clin Invest. 2008 Sep;118(9):3025-37. doi: 10.1172/JCI30836.
• [5] ACTR/AIB1 functions as an E2F1 coactivator to promote breast cancer cell proliferation and antiestrogen resistance.Mol Cell Biol. 2004 Jun;24(12):5157-71. doi: 10.1128/MCB.24.12.5157-5171.2004.
• [6] SK4 channels modulate Ca(2+) signalling and cell cycle progression in murine breast cancer.Mol Oncol. 2017 Sep;11(9):1172-1188. doi: 10.1002/1878-0261.12087. Epub 2017 Jun 26.
• [7] Identification and validation of novel prognostic markers in Renal Cell Carcinoma.Dan Med J. 2017 Oct;64(10):B5339.
• [8] Tumor-associated macrophage-derived IL-6 and IL-8 enhance invasive activity of LoVo cells induced by PRL-3 in a KCNN4 channel-dependent manner.BMC Cancer. 2014 May 10;14:330. doi: 10.1186/1471-2407-14-330.
• [9] Blockade of the intermediate-conductance Ca(2+)-activated K+ channel inhibits the angiogenesis induced by epidermal growth factor in the treatment of corneal alkali burn.Exp Eye Res. 2013 May;110:76-87. doi: 10.1016/j.exer.2013.02.015. Epub 2013 Mar 7.
• [10] Effects of Intermediate-Conductance Ca(2+)-Activated K(+) Channels on Human Endometrial Carcinoma Cells.Cell Biochem Biophys. 2015 Jun;72(2):515-25. doi: 10.1007/s12013-014-0497-0.
• [11] A proinvasive role for the Ca(2+) -activated K(+) channel KCa3.1 in malignant glioma.Glia. 2014 Jun;62(6):971-81. doi: 10.1002/glia.22655. Epub 2014 Mar 2.
• [12] The inhibitor of Ca(2+)-dependent K+ channels TRAM-34 blocks growth of hepatocellular carcinoma cells via downregulation of estrogen receptor alpha mRNA and nuclear factor-kappaB.Invest New Drugs. 2013 Apr;31(2):452-7. doi: 10.1007/s10637-012-9879-6. Epub 2012 Oct 2.
• [13] Involvement of Ca(2+)-activated K(+) channel 3.1 in hypoxia-induced pulmonary arterial hypertension and therapeutic effects of TRAM-34 in rats.Biosci Rep. 2017 Jul 27;37(4):BSR20170763. doi: 10.1042/BSR20170763. Print 2017 Aug 31.
• [14] Coactivator and corepressor gene expression in rat cerebellum during postnatal development and the effect of altered thyroid status.Endocrinology. 2000 May;141(5):1693-8. doi: 10.1210/endo.141.5.7467.
• [15] Translocation Associated Membrane Protein 1 Contributes to Chronic Constriction Injury-Induced Neuropathic Pain in the Dorsal Root Ganglion and Spinal Cord in Rats.J Mol Neurosci. 2018 Dec;66(4):535-546. doi: 10.1007/s12031-018-1187-y. Epub 2018 Oct 18.
• [16] Systemic alkalinisation delays prostate cancer cell progression in TRAMP mice.J Enzyme Inhib Med Chem. 2017 Dec;32(1):363-368. doi: 10.1080/14756366.2016.1252760.
• [17] The KCa3.1 blocker TRAM-34 inhibits proliferation of fibroblasts in paraquat-induced pulmonary fibrosis.Toxicol Lett. 2018 Oct 1;295:408-415. doi: 10.1016/j.toxlet.2018.07.020. Epub 2018 Jul 20.
• [18] The Ca?activated K?channel KCa3.1 as a potential new target for the prevention of allograft vasculopathy.PLoS One. 2013 Nov 29;8(11):e81006. doi: 10.1371/journal.pone.0081006. eCollection 2013.
• [19] Inhibition of tumor growth and metastasis by EMMPRIN multiple antigenic peptide (MAP) vaccination is mediated by immune modulation.Oncoimmunology. 2016 Nov 29;6(1):e1261778. doi: 10.1080/2162402X.2016.1261778. eCollection 2017.
• [20] The landscape of somatic chromosomal copy number aberrations in GEM models of prostate carcinoma.Mol Cancer Res. 2015 Feb;13(2):339-47. doi: 10.1158/1541-7786.MCR-14-0262. Epub 2014 Oct 8.
• [21] Obesity-associated, but not obesity-independent, tumors respond to insulin by increasing mitochondrial glucose oxidation.PLoS One. 2019 Jun 12;14(6):e0218126. doi: 10.1371/journal.pone.0218126. eCollection 2019.
• [22] Leupaxin acts as a mediator in prostate carcinoma progression through deregulation of p120catenin expression.Oncogene. 2009 Nov 12;28(45):3971-82. doi: 10.1038/onc.2009.254. Epub 2009 Aug 24.
• [23] Ca2+-Activated IK K+ Channel Blockade Radiosensitizes Glioblastoma Cells.Mol Cancer Res. 2015 Sep;13(9):1283-95. doi: 10.1158/1541-7786.MCR-15-0075. Epub 2015 Jun 3.
• [24] A TRAMP-derived orthotopic prostate syngeneic (TOPS) cancer model for investigating anti-tumor treatments.Prostate. 2018 May;78(6):457-468. doi: 10.1002/pros.23490. Epub 2018 Feb 16.
• [25] Overexpression of SOCS3 mediated by adenovirus vector in mouse and human castration-resistant prostate cancer cells increases the sensitivity to NK cells in vitro and in vivo.Cancer Gene Ther. 2019 Nov;26(11-12):388-399. doi: 10.1038/s41417-018-0075-5. Epub 2019 Jan 4.
• [26] Glipizide suppresses prostate cancer progression in the TRAMP model by inhibiting angiogenesis.Sci Rep. 2016 Jun 13;6:27819. doi: 10.1038/srep27819.
• [27] Meta-Analysis of Parkinson's Disease Transcriptome Data Using TRAM Software: Whole Substantia Nigra Tissue and Single Dopamine Neuron Differential Gene Expression.PLoS One. 2016 Sep 9;11(9):e0161567. doi: 10.1371/journal.pone.0161567. eCollection 2016.
• [28] The secreted matrix protein mindin increases prostate tumor progression and tumor-bone crosstalk via ERK 1/2 regulation.Carcinogenesis. 2019 Jul 20;40(7):828-839. doi: 10.1093/carcin/bgz105.
• [29] Impact of Time Interval between Radiation and Free Autologous Breast Reconstruction.J Reconstr Microsurg. 2017 Feb;33(2):130-136. doi: 10.1055/s-0036-1593806. Epub 2016 Oct 31.
• [30] 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.
• [31] 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.
• [32] 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.
• [33] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [34] Altered ErbB receptor signaling and gene expression in cisplatin-resistant ovarian cancer. Cancer Res. 2005 Aug 1;65(15):6789-800. doi: 10.1158/0008-5472.CAN-04-2684.
• [35] 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.
• [36] 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.
• [37] Differentially expressed genes in the prostate cancer cell line LNCaP after exposure to androgen and anti-androgen. Cancer Genet Cytogenet. 2006 Apr 15;166(2):130-8. doi: 10.1016/j.cancergencyto.2005.09.012.
• [38] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [39] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [40] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [41] 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.
• [42] 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.
• [43] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [44] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.