Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOT33IM)

• DOT Name: Retrotransposon-like protein 1 (RTL1)
• Synonyms: Mammalian retrotransposon derived protein 1; Paternally expressed gene 11 protein; Retrotransposon-derived protein PEG11
• Gene Name: RTL1
• Related Disease:
  Arthritis
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Melanocytic nevus
  Microphthalmia
  Pneumonia
  Rheumatoid arthritis
  Acute erythroid leukemia
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Alzheimer disease
  Angiomyolipoma
  Autoimmune disease
  Breast cancer
  Breast carcinoma
  Chromosomal disorder
  Cognitive impairment
  Colitis
  Fatty liver disease
  Fetal growth restriction
  Fibrosarcoma
  Hypopigmentation of the skin
  Inflammation
  Metastatic malignant neoplasm
  Metastatic melanoma
  Neuralgia
  Neuroblastoma
  Non-alcoholic fatty liver disease
  Obesity
  Periodontitis
  Psoriasis
  Severe combined immunodeficiency
  Tuberculosis
  Ulcerative colitis
  Vitiligo
  Advanced cancer
  Influenza
  Uveal Melanoma
  B-cell neoplasm
  Graft-versus-host disease
  Hepatocellular carcinoma
  Non-alcoholic steatohepatitis
  Periodontal disease
  Squamous cell carcinoma
  Stroke
  Type-1 diabetes
• UniProt ID: RTL1_HUMAN
• Pfam ID: PF16297 ; PF17919
• Sequence:
  MIEPSEDSFETMMEHKNPSSKQMESSEGSSNTTEATSGSGVRGEAGPASGPAQEKKEPPS
  GPLQEMEELPTDLLQDMEEPSSGPRKEIEDPPNDLLQDLEESCNGSHQARGDPLSGASDR
  MKEASVNPSGAREEQEAHTDLKESGREETPQEQNQTEHSTAELMAMVRSIISLYFRMQDL
  KEQQRVAEEILIKGINAGQLPAPKHFSGDRREFHEFIVLCQLTLQSYPRMFYNDRLRVGY
  VINHLSGLALEWAKALLQENSPLIGDFPAFLEAMSEVFEYRQALRVAEEAMFTIRQGGRS
  ATEYIDEFQSLVPILGWPDEVLQAHLCQGLNEEIRHYLFRVPQPDSLDSLIVLILQIEEK
  LAERRAMLRLPPEARPRNLTWIDSPAPERWMVSSWLPSEVHPDINRAHLFLLLMVRVNPY
  HSVAVQALVDSGADGNFMDEKFAQEHYVELYEKPYPQPVQSVDGSLIGNEPVWLYTEPLV
  CIHQNHQESIEFDIVPSPNFSVVLGIRWLRVHAPEVDWIKGRCTFHSPYCLKNCFRPPPP
  CIALERHGMSLLPGLPHPYSDLADVFNPKEADDETSDQPSSDGSDDLSESEPSELQQAGD
  SDHSETFYECPSTAPWEPVGARMQERARLQEEYWDLQDMLTNRQDYIQMIPELFDQLHGA
  EWFTKLELRGTIVEESVNGHRTEDVWKAAFGLELEEMKSYQPFALSPDPIIPQNVIHFIL
  KDMLGFFVLSYGQEVLIYSMSQEEHLHHVRQVLVRFRHHNVYCSLDKSQFHRQTVEFLGF
  VVTPKGVKLNKNVMTIITGYPTPGSKLSLRNFIEFVFPYRHFVERFSIIAEPLVRQLLSS
  YQFYWGVEEQEAFECLKRAFRKAPLLHHPKPQNPFYLETGVTGTALHASLIQIDDQTGKR
  ACCAFYSRNISPIEVEYSQAEMKILPIRAAFMVWCRYLENTEEPIMILLNTEDLASLNND
  RLTVLLPGHWVFFFSHFNFDVMELPEQDGGRALPPVRNLRWRRAFQRNTAARQTLLLASR
  GFPRDPSTESGEEENEEQDELNEQILRQELLAMIPIDQILNSFLAHFSMAQIRAVILHFF
  RGLLYWKNTLALAAILVLLRVRQCLSLRPAPAMRVARPQPQRSLRLILDSSLIAGSSITT
  AITQLLTQMPALVGANTIPAQELAELFLGPGRWQRNALHSQAHRGLQFTPGFWLTLCEFF
  GVRVTPQEGHLPALRQNRYLELHVVGDEDVVLREALQDDLQRYRQCGLHDGLQDTSQDKQ
  DNDVQEAPPSHTAATHPPRPRHLMDPQVLEFLGSRLLHIHSADGQLHLLSREQAARALSQ
  FLTLIYRRALPIPAWESQPREQARLEELPDEDEDANLD
• Function: Plays an essential role in capillaries endothelial cells for the maintenance of feto-maternal interface and for development of the placenta.

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthritis	DIST1YEL	Definitive	Biomarker	[1]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Definitive	Biomarker	[2]
Melanocytic nevus	DISYS32D	Definitive	Biomarker	[3]
Microphthalmia	DISGEBES	Definitive	Altered Expression	[4]
Pneumonia	DIS8EF3M	Definitive	Biomarker	[5]
Rheumatoid arthritis	DISTSB4J	Definitive	Biomarker	[1]
Acute erythroid leukemia	DISZFC1O	Strong	Genetic Variation	[6]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[7]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[7]
Alzheimer disease	DISF8S70	Strong	Biomarker	[8]
Angiomyolipoma	DIS2L71N	Strong	Biomarker	[7]
Autoimmune disease	DISORMTM	Strong	Biomarker	[9]
Breast cancer	DIS7DPX1	Strong	Biomarker	[10]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[10]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[11]
Cognitive impairment	DISH2ERD	Strong	Biomarker	[8]
Colitis	DISAF7DD	Strong	Biomarker	[5]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[12]
Fetal growth restriction	DIS5WEJ5	Strong	Posttranslational Modification	[13]
Fibrosarcoma	DISWX7MU	Strong	Genetic Variation	[14]
Hypopigmentation of the skin	DIS39YKC	Strong	Biomarker	[15]
Inflammation	DISJUQ5T	Strong	Biomarker	[16]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[17]
Metastatic melanoma	DISSL43L	Strong	Biomarker	[18]
Neuralgia	DISWO58J	Strong	Biomarker	[19]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[20]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[12]
Obesity	DIS47Y1K	Strong	Biomarker	[21]
Periodontitis	DISI9JOI	Strong	Altered Expression	[22]
Psoriasis	DIS59VMN	Strong	Biomarker	[16]
Severe combined immunodeficiency	DIS6MF4Q	Strong	Altered Expression	[23]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[24]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[25]
Vitiligo	DISR05SL	Strong	Biomarker	[26]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[27]
Influenza	DIS3PNU3	moderate	Biomarker	[28]
Uveal Melanoma	DISA7ZGL	Disputed	Biomarker	[29]
B-cell neoplasm	DISVY326	Limited	Altered Expression	[30]
Graft-versus-host disease	DIS0QADF	Limited	Biomarker	[31]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[30]
Non-alcoholic steatohepatitis	DIST4788	Limited	Biomarker	[32]
Periodontal disease	DISJQHVN	Limited	Altered Expression	[22]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[33]
Stroke	DISX6UHX	Limited	Biomarker	[34]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Retrotransposon-like protein 1 (RTL1).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Retrotransposon-like protein 1 (RTL1).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Retrotransposon-like protein 1 (RTL1).	[37]
UNC0379	DMD1E4J	Preclinical	UNC0379 decreases the expression of Retrotransposon-like protein 1 (RTL1).	[39]
chlordane	DMMHU8G	Investigative	chlordane increases the expression of Retrotransposon-like protein 1 (RTL1).	[37]

References

• [1] Maresin 1 improves the Treg/Th17 imbalance in rheumatoid arthritis through miR-21.Ann Rheum Dis. 2018 Nov;77(11):1644-1652. doi: 10.1136/annrheumdis-2018-213511. Epub 2018 Jul 25.
• [2] Emergence of a cell line with extreme hypodiploidy in blast crisis of chronic myelocytic leukemia.Blood. 1979 Apr;53(4):707-11.
• [3] Immunohistochemical CD271 expression correlates with melanoma progress in a case-control study.Pathology. 2018 Jun;50(4):402-410. doi: 10.1016/j.pathol.2017.12.340. Epub 2018 Apr 17.
• [4] Human cutaneous melanomas lacking MITF and melanocyte differentiation antigens express a functional Axl receptor kinase.J Invest Dermatol. 2011 Dec;131(12):2448-57. doi: 10.1038/jid.2011.218. Epub 2011 Jul 28.
• [5] Maresin 1 mitigates concanavalin A-induced acute liver injury in mice by inhibiting ROS-mediated activation of NF-B signaling.Free Radic Biol Med. 2020 Feb 1;147:23-36. doi: 10.1016/j.freeradbiomed.2019.11.033. Epub 2019 Nov 27.
• [6] Isochromosome 21 and other chromosomal abnormalities in a patient with erythroleukaemia.Ann Genet. 1983;26(4):240-2.
• [7] Immunohistochemical and reverse transcription-polymerase chain reaction expression analysis of tyrosinase and microphthalmia-associated transcription factor in angiomyolipomas.Appl Immunohistochem Mol Morphol. 2001 Mar;9(1):29-34.
• [8] DHA Selectively Protects SAMP-8-Associated Cognitive Deficits Through Inhibition of JNK.Mol Neurobiol. 2019 Mar;56(3):1618-1627. doi: 10.1007/s12035-018-1185-7. Epub 2018 Jun 17.
• [9] Melanocyte lysis by cytotoxic T lymphocytes recognizing the MART-1 melanoma antigen in HLA-A2 patients with Vogt-Koyanagi-Harada disease.Int Immunol. 1996 May;8(5):799-803. doi: 10.1093/intimm/8.5.799.
• [10] False-positive cells in sentinel lymph nodes.Semin Diagn Pathol. 2008 May;25(2):116-9. doi: 10.1053/j.semdp.2008.03.001.
• [11] Genomic stability and functional activity may be lost in telomerase-transduced human CD8+ T lymphocytes.Blood. 2005 Oct 15;106(8):2663-70. doi: 10.1182/blood-2004-09-3742. Epub 2005 Jul 7.
• [12] Maresin 1 attenuates NAFLD by suppression of endoplasmic reticulum stress via AMPK-SERCA2b pathway.J Biol Chem. 2018 Mar 16;293(11):3981-3988. doi: 10.1074/jbc.RA117.000885. Epub 2018 Feb 5.
• [13] DNA methylation of the Rtl1 promoter in the placentas with fetal growth restriction.Pediatr Neonatol. 2019 Oct;60(5):512-516. doi: 10.1016/j.pedneo.2019.01.001. Epub 2019 Jan 5.
• [14] Genetic immunization for the melanoma antigen MART-1/Melan-A using recombinant adenovirus-transduced murine dendritic cells.Cancer Res. 1997 Jul 15;57(14):2865-9.
• [15] Differential expression of inhibitory or activating CD94/NKG2 subtypes on MART-1-reactive T cells in vitiligo versus melanoma: a case report.J Invest Dermatol. 2002 Apr;118(4):595-9. doi: 10.1046/j.1523-1747.2002.01698.x.
• [16] Maresin-1 suppresses imiquimod-induced skin inflammation by regulating IL-23 receptor expression.Sci Rep. 2018 Apr 3;8(1):5522. doi: 10.1038/s41598-018-23623-9.
• [17] Prognostic relevance of circulating tumor cells in metastatic uveal melanoma.Oncology. 2011;80(1-2):57-62. doi: 10.1159/000328283. Epub 2011 May 31.
• [18] Metastatic melanoma with dedifferentiation and extensive rhabdomyosarcomatous heterologous component.J Cutan Pathol. 2018 May;45(5):360-364. doi: 10.1111/cup.13122. Epub 2018 Mar 1.
• [19] Pro-resolving mediator maresin 1 ameliorates pain hypersensitivity in a rat spinal nerve ligation model of neuropathic pain.J Pain Res. 2018 Aug 10;11:1511-1519. doi: 10.2147/JPR.S160779. eCollection 2018.
• [20] Expression of MAGE-1, MAGE-3 and MART-1 genes in neuroblastoma.Int J Cancer. 1996 Oct 21;69(5):403-7. doi: 10.1002/(SICI)1097-0215(19961021)69:5<403::AID-IJC9>3.0.CO;2-9.
• [21] Maresin 1 inhibits TNF-alpha-induced lipolysis and autophagy in 3T3-L1 adipocytes.J Cell Physiol. 2018 Mar;233(3):2238-2246. doi: 10.1002/jcp.26096. Epub 2017 Aug 30.
• [22] Salivary levels of specialized pro-resolving lipid mediators as indicators of periodontal health/disease status.J Clin Periodontol. 2019 Oct;46(10):978-990. doi: 10.1111/jcpe.13173. Epub 2019 Aug 20.
• [23] Adoptive transfer of an anti-MART-1(27-35)-specific CD8+ T cell clone leads to immunoselection of human melanoma antigen-loss variants in SCID mice.Eur J Immunol. 2003 Feb;33(2):556-66. doi: 10.1002/immu.200310032.
• [24] Resolvin D1 (RvD1) and maresin 1 (Mar1) contribute to human macrophage control of M. tuberculosis infection while resolving inflammation.Int Immunopharmacol. 2019 Sep;74:105694. doi: 10.1016/j.intimp.2019.105694. Epub 2019 Jun 19.
• [25] Maresin 1 alleviates dextran sulfate sodium-induced ulcerative colitis by regulating NRF2 and TLR4/NF-kB signaling pathway.Int Immunopharmacol. 2020 Jan;78:106018. doi: 10.1016/j.intimp.2019.106018. Epub 2019 Nov 25.
• [26] Autoantibodies in vitiligo patients are not directed to the melanocyte differentiation antigen MelanA/MART1.Clin Exp Immunol. 2002 Sep;129(3):527-32. doi: 10.1046/j.1365-2249.2002.01949.x.
• [27] Immunotherapy Resistance by Inflammation-Induced Dedifferentiation.Cancer Discov. 2018 Aug;8(8):935-943. doi: 10.1158/2159-8290.CD-17-1178. Epub 2018 Jun 13.
• [28] Soluble human LAG-3 molecule amplifies the in vitro generation of type 1 tumor-specific immunity.Cancer Res. 2006 Apr 15;66(8):4450-60. doi: 10.1158/0008-5472.CAN-05-2728.
• [29] Targeted silencing of MART-1 gene expression by RNA interference enhances the migration ability of uveal melanoma cells.Int J Mol Sci. 2013 Jul 19;14(7):15092-104. doi: 10.3390/ijms140715092.
• [30] Hepatitis B Virus-Upregulated LNC-HUR1 Promotes Cell Proliferation and Tumorigenesis by Blocking p53 Activity.Hepatology. 2018 Dec;68(6):2130-2144. doi: 10.1002/hep.30098. Epub 2018 Sep 19.
• [31] Human PBMC-transferred murine MHC class I/II-deficient NOG mice enable long-term evaluation of human immune responses.Cell Mol Immunol. 2018 Nov;15(11):953-962. doi: 10.1038/cmi.2017.106. Epub 2017 Nov 20.
• [32] Resolving inflammation in nonalcoholic steatohepatitis.J Clin Invest. 2019 Mar 11;129(4):1524-1526. doi: 10.1172/JCI127583. eCollection 2019 Mar 11.
• [33] Cutaneous neoplasms composed of melanoma and carcinoma: A rare but important diagnostic pitfall and review of the literature.J Cutan Pathol. 2020 Jan;47(1):36-46. doi: 10.1111/cup.13551. Epub 2019 Aug 11.
• [34] Unified nexus of macrophages and maresins in cardiac reparative mechanisms.FASEB J. 2018 Oct;32(10):5227-5237. doi: 10.1096/fj.201800254R. Epub 2018 May 11.
• [35] Role of DNA methylation at the placental RTL1 gene locus in type 1 diabetes.Pediatr Diabetes. 2017 May;18(3):178-187. doi: 10.1111/pedi.12387. Epub 2016 May 13.
• [36] 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.
• [37] Xenobiotic CAR activators induce Dlk1-Dio3 locus noncoding RNA expression in mouse liver. Toxicol Sci. 2017 Aug 1;158(2):367-378.
• [38] 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.
• [39] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.