Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT14QP7N)

• DOT Name: Putative lipid scramblase CLPTM1 (CLPTM1)
• Synonyms: Cleft lip and palate transmembrane protein 1
• Gene Name: CLPTM1
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Cleft lip/palate
  Pancreatic tumour
  Prostate neoplasm
  Lung cancer
  Lung carcinoma
  Melanoma
  Neoplasm
  Non-small-cell lung cancer
• UniProt ID: CLPT1_HUMAN
• Pfam ID: PF05602
• Sequence:
  MAAAQEADGARSAVVAAGGGSSGQVTSNGSIGRDPPAETQPQNPPAQPAPNAWQVIKGVL
  FRIFIIWAISSWFRRGPAPQDQAGPGGAPRVASRNLFPKDTLMNLHVYISEHEHFTDFNA
  TSALFWEQHDLVYGDWTSGENSDGCYEHFAELDIPQSVQQNGSIYIHVYFTKSGFHPDPR
  QKALYRRLATVHMSRMINKYKRRRFQKTKNLLTGETEADPEMIKRAEDYGPVEVISHWHP
  NITINIVDDHTPWVKGSVPPPLDQYVKFDAVSGDYYPIIYFNDYWNLQKDYYPINESLAS
  LPLRVSFCPLSLWRWQLYAAQSTKSPWNFLGDELYEQSDEEQDSVKVALLETNPYLLALT
  IIVSIVHSVFEFLAFKNDIQFWNSRQSLEGLSVRSVFFGVFQSFVVLLYILDNETNFVVQ
  VSVFIGVLIDLWKITKVMDVRLDREHRVAGIFPRLSFKDKSTYIESSTKVYDDMAFRYLS
  WILFPLLGCYAVYSLLYLEHKGWYSWVLSMLYGFLLTFGFITMTPQLFINYKLKSVAHLP
  WRMLTYKALNTFIDDLFAFVIKMPVMYRIGCLRDDVVFFIYLYQRWIYRVDPTRVNEFGM
  SGEDPTAAAPVAEVPTAAGALTPTPAPTTTTATREEASTSLPTKPTQGASSASEPQEAPP
  KPAEDKKKD
• Function: Involved in GABAergic but not glutamatergic transmission. Binds and traps GABAA receptors in the endoplasmic reticulum (ER). Modulates postsynaptic GABAergic transmission, and therefore inhibitory neurotransmission, by reducing the plasma membrane expression of these receptors. Altered GABAergic signaling is one among many causes of cleft palate. Might function as a lipid scramblase, translocating lipids in membranes from one leaflet to the other one. Required for efficient glycosylphosphatidylinositol (GPI) inositol deacylation in the ER, which is a crucial step to switch GPI-anchored proteins (GPI-APs) from protein folding to transport states. May play a role in T-cell development.
• Tissue Specificity: Widely expressed.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Cleft lip/palate	DIS14IG3	Strong	Genetic Variation	[3]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[4]
Prostate neoplasm	DISHDKGQ	Strong	Genetic Variation	[3]
Lung cancer	DISCM4YA	moderate	Genetic Variation	[5]
Lung carcinoma	DISTR26C	moderate	Genetic Variation	[5]
Melanoma	DIS1RRCY	moderate	Genetic Variation	[6]
Neoplasm	DISZKGEW	moderate	Biomarker	[7]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Putative lipid scramblase CLPTM1 (CLPTM1) affects the response to substance of Doxorubicin.	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Putative lipid scramblase CLPTM1 (CLPTM1).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Putative lipid scramblase CLPTM1 (CLPTM1).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Putative lipid scramblase CLPTM1 (CLPTM1).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Putative lipid scramblase CLPTM1 (CLPTM1).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Putative lipid scramblase CLPTM1 (CLPTM1).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of Putative lipid scramblase CLPTM1 (CLPTM1).	[14]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Putative lipid scramblase CLPTM1 (CLPTM1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Putative lipid scramblase CLPTM1 (CLPTM1).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Putative lipid scramblase CLPTM1 (CLPTM1).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Putative lipid scramblase CLPTM1 (CLPTM1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Putative lipid scramblase CLPTM1 (CLPTM1).	[19]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Putative lipid scramblase CLPTM1 (CLPTM1).	[20]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Putative lipid scramblase CLPTM1 (CLPTM1).	[17]

References

• [1] The association of telomere length and genetic variation in telomere biology genes.Hum Mutat. 2010 Sep;31(9):1050-8. doi: 10.1002/humu.21314.
• [2] Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.Nat Genet. 2019 Mar;51(3):404-413. doi: 10.1038/s41588-018-0311-9. Epub 2019 Jan 7.
• [3] Identification of inactivating mutations in the JAK1, SYNJ2, and CLPTM1 genes in prostate cancer cells using inhibition of nonsense-mediated decay and microarray analysis.Cancer Genet Cytogenet. 2005 Sep;161(2):97-103. doi: 10.1016/j.cancergencyto.2005.02.006.
• [4] Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer.Nat Genet. 2015 Aug;47(8):911-6. doi: 10.1038/ng.3341. Epub 2015 Jun 22.
• [5] Genetic polymorphisms in the TERT-CLPTM1L region and lung cancer susceptibility in Chinese males.Oncol Lett. 2017 Aug;14(2):1588-1594. doi: 10.3892/ol.2017.6289. Epub 2017 Jun 1.
• [6] Long telomere length and a TERT-CLPTM1 locus polymorphism association with melanoma risk.Eur J Cancer. 2014 Dec;50(18):3168-77. doi: 10.1016/j.ejca.2014.09.017. Epub 2014 Oct 31.
• [7] Gene expression profile associated with response to doxorubicin-based therapy in breast cancer. Clin Cancer Res. 2005 Oct 15;11(20):7434-43. doi: 10.1158/1078-0432.CCR-04-0548.
• [8] A TERT-CLPTM1 locus polymorphism (rs401681) is associated with EGFR mutation in non-small cell lung cancer.Pathol Res Pract. 2017 Nov;213(11):1340-1343. doi: 10.1016/j.prp.2017.09.028. Epub 2017 Oct 7.
• [9] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [10] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [11] 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.
• [12] 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.
• [13] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [14] 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.
• [15] 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.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] 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.
• [20] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [21] Gene expression profile associated with response to doxorubicin-based therapy in breast cancer. Clin Cancer Res. 2005 Oct 15;11(20):7434-43. doi: 10.1158/1078-0432.CCR-04-0548.