Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJUS74N)

• DOT Name: Derlin-1 (DERL1)
• Synonyms: Degradation in endoplasmic reticulum protein 1; DERtrin-1; Der1-like protein 1
• Gene Name: DERL1
• Related Disease:
  Acute lymphocytic leukaemia
  Angelman syndrome
  Acute erythroid leukemia
  Acute myelogenous leukaemia
  Acute myelomonocytic leukemia M4
  Advanced cancer
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Chromosomal disorder
  Esophageal squamous cell carcinoma
  Glioma
  Hematologic disease
  Lung cancer
  Lung carcinoma
  Myelodysplastic syndrome
  Myeloid leukaemia
  Neoplasm
  Non-small-cell lung cancer
  Pancytopenia
  Plasma cell myeloma
  Polycythemia vera
  Primary myelofibrosis
  Stevens-Johnson syndrome
  Thrombocytopenia
  Toxic epidermal necrolysis
  Urinary bladder cancer
  Urinary bladder neoplasm
  Amyotrophic lateral sclerosis
  Colon cancer
  Essential thrombocythemia
  Head-neck squamous cell carcinoma
  Myelofibrosis
  Childhood myelodysplastic syndrome
  Lymphoid leukemia
  Osteomyelitis
  Pyoderma gangrenosum
• UniProt ID: DERL1_HUMAN
• PDB ID: 5GLF; 7CZB; 7Y4W; 7Y53; 7Y59
• Pfam ID: PF04511
• Sequence:
  MSDIGDWFRSIPAITRYWFAATVAVPLVGKLGLISPAYLFLWPEAFLYRFQIWRPITATF
  YFPVGPGTGFLYLVNLYFLYQYSTRLETGAFDGRPADYLFMLLFNWICIVITGLAMDMQL
  LMIPLIMSVLYVWAQLNRDMIVSFWFGTRFKACYLPWVILGFNYIIGGSVINELIGNLVG
  HLYFFLMFRYPMDLGGRNFLSTPQFLYRWLPSRRGGVSGFGVPPASMRRAADQNGGGGRH
  NWGQGFRLGDQ
• Function: Functional component of endoplasmic reticulum-associated degradation (ERAD) for misfolded lumenal proteins. Forms homotetramers which encircle a large channel traversing the endoplasmic reticulum (ER) membrane. This allows the retrotranslocation of misfolded proteins from the ER into the cytosol where they are ubiquitinated and degraded by the proteasome. The channel has a lateral gate within the membrane which provides direct access to membrane proteins with no need to reenter the ER lumen first. May mediate the interaction between VCP and the misfolded protein. Also involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation. By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway ; (Microbial infection) In case of infection by cytomegaloviruses, it plays a central role in the export from the ER and subsequent degradation of MHC class I heavy chains via its interaction with US11 viral protein, which recognizes and associates with MHC class I heavy chains. Also participates in the degradation process of misfolded cytomegalovirus US2 protein.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Protein processing in endoplasmic reticulum (hsa04141)
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  N-glycan trimming in the ER and Calnexin/Calreticulin cycle (R-HSA-532668)
  Defective CFTR causes cystic fibrosis (R-HSA-5678895)
  E3 ubiquitin ligases ubiquitinate target proteins (R-HSA-8866654)
  ABC-family proteins mediated transport (R-HSA-382556)

Molecular Interaction Atlas (MIA) of This DOT

38 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Definitive	Genetic Variation	[1]
Angelman syndrome	DIS4QVXO	Definitive	Genetic Variation	[2]
Acute erythroid leukemia	DISZFC1O	Strong	Genetic Variation	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[4]
Acute myelomonocytic leukemia M4	DISRRMV2	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[6]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[6]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[7]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[7]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[8]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[9]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[10]
Glioma	DIS5RPEH	Strong	Altered Expression	[11]
Hematologic disease	DIS9XD9A	Strong	Genetic Variation	[12]
Lung cancer	DISCM4YA	Strong	Altered Expression	[13]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[13]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[14]
Myeloid leukaemia	DISMN944	Strong	Genetic Variation	[15]
Neoplasm	DISZKGEW	Strong	Altered Expression	[16]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[17]
Pancytopenia	DISVKEHV	Strong	Genetic Variation	[18]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[19]
Polycythemia vera	DISB5FPO	Strong	Biomarker	[20]
Primary myelofibrosis	DIS6L0CN	Strong	Genetic Variation	[4]
Stevens-Johnson syndrome	DISZG4YX	Strong	Biomarker	[21]
Thrombocytopenia	DISU61YW	Strong	Genetic Variation	[22]
Toxic epidermal necrolysis	DISIWPFR	Strong	Biomarker	[21]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[6]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Biomarker	[23]
Colon cancer	DISVC52G	moderate	Altered Expression	[24]
Essential thrombocythemia	DISWWK11	moderate	Genetic Variation	[4]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[24]
Myelofibrosis	DISIMP21	moderate	Genetic Variation	[4]
Childhood myelodysplastic syndrome	DISMN80I	Disputed	Genetic Variation	[25]
Lymphoid leukemia	DIS65TYQ	Limited	Genetic Variation	[26]
Osteomyelitis	DIS0VUZL	Limited	Genetic Variation	[9]
Pyoderma gangrenosum	DIS8QVTT	Limited	Genetic Variation	[9]

7 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 Derlin-1 (DERL1).	[27]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Derlin-1 (DERL1).	[28]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Derlin-1 (DERL1).	[29]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Derlin-1 (DERL1).	[30]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Derlin-1 (DERL1).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Derlin-1 (DERL1).	[33]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Derlin-1 (DERL1).	[34]

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 Derlin-1 (DERL1).	[32]

References

• [1] Characterization of a novel acquired der(1)del(1)(p13p31)t(1;15)(q42;q15) in a high risk t(12;21)-positive acute lymphoblastic leukemia.Gene. 2016 Dec 20;595(1):39-48. doi: 10.1016/j.gene.2016.09.030. Epub 2016 Sep 21.
• [2] Girl with monosomy 1p36 and Angelman syndrome due to unbalanced der(1) transmission of a maternal translocation t(1;15)(p36.3;q13.1).Am J Med Genet A. 2004 Nov 15;131(1):94-8. doi: 10.1002/ajmg.a.30413.
• [3] Derivative (1;7)(q10;p10) in a patient with de novo acute erythroblastic leukemia (AML-M6).Cancer Genet Cytogenet. 1999 Nov;115(1):62-4. doi: 10.1016/s0165-4608(99)00076-x.
• [4] Translocation t(1;9) is a recurrent cytogenetic abnormality associated with progression of essential thrombocythemia patients displaying the JAK2 V617F mutation.Leuk Res. 2011 Sep;35(9):1188-92. doi: 10.1016/j.leukres.2011.02.001. Epub 2011 Mar 3.
• [5] Myelodysplastic syndrome that progressed to acute myelomonocytic leukemia with eosinophilia showing peculiar chromosomal abnormality: a case report.J Korean Med Sci. 1999 Aug;14(4):448-50. doi: 10.3346/jkms.1999.14.4.448.
• [6] Derlin-1 overexpression confers poor prognosis in muscle invasive bladder cancer and contributes to chemoresistance and invasion through PI3K/AKT and ERK/MMP signaling.Oncotarget. 2017 Mar 7;8(10):17059-17069. doi: 10.18632/oncotarget.15001.
• [7] Derlin-1 functions as a growth promoter in breast cancer.Biol Chem. 2020 Feb 25;401(3):377-387. doi: 10.1515/hsz-2018-0442.
• [8] Derlin-1 is overexpressed in human breast carcinoma and protects cancer cells from endoplasmic reticulum stress-induced apoptosis.Breast Cancer Res. 2008;10(1):R7. doi: 10.1186/bcr1849. Epub 2008 Jan 20.
• [9] Association of pyoderma gangrenosum and sterile osteomyelitis in a patient having myelodysplastic syndrome with der(1;7)(q10;q10).Eur J Haematol. 2004 Feb;72(2):149-53. doi: 10.1046/j.0902-4441.2003.00191.x.
• [10] Derlin-1 is a target to improve radiotherapy effect of esophageal squamous cell carcinoma.Oncotarget. 2017 Jul 7;8(33):55135-55146. doi: 10.18632/oncotarget.19069. eCollection 2017 Aug 15.
• [11] TTBK2 circular RNA promotes glioma malignancy by regulating miR-217/HNF1/Derlin-1 pathway.J Hematol Oncol. 2017 Feb 20;10(1):52. doi: 10.1186/s13045-017-0422-2.
• [12] Unbalanced 1;7 translocation and therapy-induced hematologic disorders: a possible relationship.Am J Hematol. 1986 Jan;21(1):39-47. doi: 10.1002/ajh.2830210106.
• [13] Derlin-1 is overexpressed in non-small cell lung cancer and promotes cancer cell invasion via EGFR-ERK-mediated up-regulation of MMP-2 and MMP-9.Am J Pathol. 2013 Mar;182(3):954-64. doi: 10.1016/j.ajpath.2012.11.019. Epub 2013 Jan 7.
• [14] Derivative (1)t(1;16)(p11;p11.1) in myelodysplastic syndrome: a case report and review of the literature.Cancer Genet Cytogenet. 2010 Jan 1;196(1):89-92. doi: 10.1016/j.cancergencyto.2009.07.003.
• [15] Molecular cytogenetic analysis of complex karyotypes with derivative chromosome der(1)t(1;5) found in two patients with myeloid leukemia.Cancer Genet Cytogenet. 2007 Jul 15;176(2):150-5. doi: 10.1016/j.cancergencyto.2007.05.001.
• [16] MicroRNA-181d is a tumor suppressor in human esophageal squamous cell carcinoma inversely regulating Derlin-1.Oncol Rep. 2016 Oct;36(4):2041-8. doi: 10.3892/or.2016.5028. Epub 2016 Aug 22.
• [17] MiR-598 Suppresses Invasion and Migration by Negative Regulation of Derlin-1 and Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer.Cell Physiol Biochem. 2018;47(1):245-256. doi: 10.1159/000489803. Epub 2018 May 11.
• [18] Unbalanced 1;7 translocation in myelodysplastic syndrome following treatment of acute myeloblastic leukemia with an 8;21 translocation.Cancer Genet Cytogenet. 1994 May;74(1):35-9. doi: 10.1016/0165-4608(94)90026-4.
• [19] A der(1;15)(q10;q10) is a rare nonrandom whole-arm translocation in patients with acute lymphoblastic leukemia.Cancer Genet Cytogenet. 2007 Dec;179(2):132-5. doi: 10.1016/j.cancergencyto.2007.08.008.
• [20] der(1)t(1;9): a specific chromosome abnormality in polycythemia vera? Cytogenetic and in situ hybridization studies.Cancer Genet Cytogenet. 1989 Jul 1;40(1):121-7. doi: 10.1016/0165-4608(89)90153-2.
• [21] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [22] Comprehensive analysis of isolated der(1;7)(q10;p10) in a large international homogenous cohort of patients with myelodysplastic syndromes.Genes Chromosomes Cancer. 2019 Oct;58(10):689-697. doi: 10.1002/gcc.22760. Epub 2019 Apr 30.
• [23] A small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model.Nat Commun. 2018 Jul 10;9(1):2668. doi: 10.1038/s41467-018-05127-2.
• [24] Elevated expression of Derlin-1 associates with unfavorable survival time of squamous cell carcinoma of the head and neck and promotes its malignance.J Cancer. 2017 Jul 21;8(12):2336-2345. doi: 10.7150/jca.19411. eCollection 2017.
• [25] Recurrent unbalanced whole-arm t(1;10)(q10;p10) in myelodysplastic syndrome: a case report and literature review.Cancer Genet Cytogenet. 2007 Jan 15;172(2):165-7. doi: 10.1016/j.cancergencyto.2006.09.022.
• [26] Secondary chromosomal abnormalities in acute leukemias.Leukemia. 1994 Jun;8(6):953-62.
• [27] 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.
• [28] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [29] 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.
• [30] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [31] 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.
• [32] 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.
• [33] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [34] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.