Details of Drug Off-Target (DOT)

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

• DOT Name: Melanoma inhibitory activity protein 2 (MIA2)
• Synonyms: MIA protein 2; CTAGE family member 5 ER export factor; Cutaneous T-cell lymphoma-associated antigen 5; Meningioma-expressed antigen 6/11
• Gene Name: MIA2
• Related Disease:
  Melanoma
  Advanced cancer
  Basal ganglia calcification, idiopathic, 1
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Lung squamous cell carcinoma
  Matthew-Wood syndrome
  Meningioma
  Pancreatic adenocarcinoma
  Primary cutaneous T-cell lymphoma
  Squamous cell carcinoma
  Cervical Intraepithelial neoplasia
  Neoplasm
• UniProt ID: MIA2_HUMAN
• Pfam ID: PF07653
• Sequence:
  MAKFGVHRILLLAISLTKCLESTKLLADLKKCGDLECEALINRVSAMRDYRGPDCRYLNF
  TKGEEISVYVKLAGEREDLWAGSKGKEFGYFPRDAVQIEEVFISEEIQMSTKESDFLCLL
  GVSYTFDNEDSELNGDYGENIYPYEEDKDEKSSIYESDFQIEPGFYATYESTLFEDQVPA
  LEAPEDIGSTSESKDWEEVVVESMEQDRIPEVHVPPSSAVSGVKEWFGLGGEQAEEKAFE
  SVIEPVQESSFRSRKIAVEDENDLEELNNGEPQTEHQQESESEIDSVPKTQSELASESEH
  IPKPQSTGWFGGGFTSYLGFGDEDTGLELIAEESNPPLQDFPNSISSDKEATVPCTEILT
  EKKDTITNDSLSLKPSWFDFGFAILGFAYAKEDKIMLDDRKNEEDGGADEHEHPLTSELD
  PEKEQEIETIKIIETEDQIDKKPVSEKTDESDTIPYLKKFLYNFDNPWNFQNIPKETELP
  FPKQILDQNNVIENEETGEFSIDNYPTDNTKVMIFKSSYSLSDMVSNIELPTRIHEEVYF
  EPSSSKDSDENSKPSVDTEGPALVEIDRSVENTLLNSQMVSTDNSLSSQNYISQKEDASE
  FQILKYLFQIDVYDFMNSAFSPIVILTERVVAALPEGMRPDSNLYGFPWELVICAAVVGF
  FAVLFFLWRSFRSVRSRLYVGREKKLALMLSGLIEEKSKLLEKFSLVQKEYEGYEVESSL
  KDASFEKEATEAQSLEATCEKLNRSNSELEDEILCLEKELKEEKSKHSEQDELMADISKR
  IQSLEDESKSLKSQVAEAKMTFKIFQMNEERLKIAIKDALNENSQLQESQKQLLQEAEVW
  KEQVSELNKQKVTFEDSKVHAEQVLNDKESHIKTLTERLLKMKDWAAMLGEDITDDDNLE
  LEMNSESENGAYLDNPPKGALKKLIHAAKLNASLKTLEGERNQIYIQLSEVDKTKEELTE
  HIKNLQTEQASLQSENTHFENENQKLQQKLKVMTELYQENEMKLHRKLTVEENYRLEKEE
  KLSKVDEKISHATEELETYRKRAKDLEEELERTIHSYQGQIISHEKKAHDNWLAARNAER
  NLNDLRKENAHNRQKLTETELKFELLEKDPYALDVPNTAFGREHSPYGPSPLGWPSSETR
  AFLSPPTLLEGPLRLSPLLPGGGGRGSRGPGNPLDHQITNERGESSCDRLTDPHRAPSDT
  GSLSPPWDQDRRMMFPPPGQSYPDSALPPQRQDRFCSNSGRLSGPAELRSFNMPSLDKMD
  GSMPSEMESSRNDTKDDLGNLNVPDSSLPAENEATGPGFVPPPLAPIRGPLFPVDARGPF
  LRRGPPFPPPPPGAMFGASRDYFPPGDFPGPPPAPFAMRNVYPPRGFPPYLPPRPGFFPP
  PPHSEGRSEFPSGLIPPSNEPATEHPEPQQET
• Function: Plays a role in the transport of cargos that are too large to fit into COPII-coated vesicles and require specific mechanisms to be incorporated into membrane-bound carriers and exported from the endoplasmic reticulum. Plays a role in the secretion of lipoproteins, pre-chylomicrons and pre-VLDLs, by participating in their export from the endoplasmic reticulum. Thereby, may play a role in cholesterol and triglyceride homeostasis. Required for collagen VII (COL7A1) secretion by loading COL7A1 into transport carriers and recruiting PREB/SEC12 at the endoplasmic reticulum exit sites.
• Tissue Specificity: Highly expressed in liver and weakly in testis. Expression was higher in patients with severe fibrosis or inflammation and chronic hepatitis . Isoform 1 is specifically expressed in lung, testis, small intestine, colon, pancreas, kidney, liver and prostate . Isoform 8 is expressed only in testis (at the protein level). Isoform 8 (at protein level) and isoform 9 are expressed in cutaneous T-cell lymphoma (CTCL) cell lines, colorectal carcinomas, breast carcinomas and melanoma. Isoform 9, but not isoform 5A, is expressed in head and neck squamous cell carcinoma .
• Reactome Pathway: Cargo concentration in the ER (R-HSA-5694530)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma	DIS1RRCY	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Basal ganglia calcification, idiopathic, 1	DIS44NTG	Strong	Genetic Variation	[3]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Lung squamous cell carcinoma	DISXPIBD	Strong	Genetic Variation	[5]
Matthew-Wood syndrome	DISA7HR7	Strong	Genetic Variation	[6]
Meningioma	DISPT4TG	Strong	Altered Expression	[7]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Genetic Variation	[6]
Primary cutaneous T-cell lymphoma	DIS35WVW	Strong	Biomarker	[8]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[9]
Cervical Intraepithelial neoplasia	DISXP757	Limited	Altered Expression	[2]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Melanoma inhibitory activity protein 2 (MIA2).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Melanoma inhibitory activity protein 2 (MIA2).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Melanoma inhibitory activity protein 2 (MIA2).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Melanoma inhibitory activity protein 2 (MIA2).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Melanoma inhibitory activity protein 2 (MIA2).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Melanoma inhibitory activity protein 2 (MIA2).	[15]
Menadione	DMSJDTY	Approved	Menadione increases the expression of Melanoma inhibitory activity protein 2 (MIA2).	[15]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Melanoma inhibitory activity protein 2 (MIA2).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Melanoma inhibitory activity protein 2 (MIA2).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Melanoma inhibitory activity protein 2 (MIA2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Melanoma inhibitory activity protein 2 (MIA2).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Melanoma inhibitory activity protein 2 (MIA2).	[21]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Melanoma inhibitory activity protein 2 (MIA2).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Melanoma inhibitory activity protein 2 (MIA2).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Melanoma inhibitory activity protein 2 (MIA2).	[19]

References

• [1] The importance of melanoma inhibitory activity gene family in the tumor progression of oral cancer.Pathol Int. 2018 May;68(5):278-286. doi: 10.1111/pin.12672. Epub 2018 Apr 14.
• [2] A comprehensive expression analysis of the MIA gene family in malignancies: MIA gene family members are novel, useful markers of esophageal, lung, and cervical squamous cell carcinoma.Oncotarget. 2016 May 24;7(21):31137-52. doi: 10.18632/oncotarget.9082.
• [3] Analysis of the CTAGE5 P521A variation with the risk of familial idiopathic basal ganglia calcification in an Iranian population.J Mol Neurosci. 2013 Mar;49(3):614-7. doi: 10.1007/s12031-012-9898-y. Epub 2012 Oct 5.
• [4] The X protein of hepatitis B virus activates hepatoma cell proliferation through repressing melanoma inhibitory activity 2 gene.Biochem Biophys Res Commun. 2011 Dec 16;416(3-4):379-84. doi: 10.1016/j.bbrc.2011.11.046. Epub 2011 Nov 19.
• [5] Genomic variations in the counterpart normal controls of lung squamous cell carcinomas.Front Med. 2018 Jun;12(3):280-288. doi: 10.1007/s11684-017-0580-1. Epub 2017 Nov 28.
• [6] A common genetic variation of melanoma inhibitory activity-2 labels a subtype of pancreatic adenocarcinoma with high endoplasmic reticulum stress levels.Sci Rep. 2015 Feb 6;5:8109. doi: 10.1038/srep08109.
• [7] MEA6 Deficiency Impairs Cerebellar Development and Motor Performance by Tethering Protein Trafficking.Front Cell Neurosci. 2019 Jun 11;13:250. doi: 10.3389/fncel.2019.00250. eCollection 2019.
• [8] cTAGE: a cutaneous T cell lymphoma associated antigen family with tumor-specific splicing.J Invest Dermatol. 2003 Jul;121(1):198-206. doi: 10.1046/j.1523-1747.2003.12318.x.
• [9] Protumoral roles of melanoma inhibitory activity 2 in oral squamous cell carcinoma.Br J Cancer. 2013 Apr 16;108(7):1460-9. doi: 10.1038/bjc.2013.27. Epub 2013 Mar 19.
• [10] 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.
• [11] 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.
• [12] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [15] Gene expression after treatment with hydrogen peroxide, menadione, or t-butyl hydroperoxide in breast cancer cells. Cancer Res. 2002 Nov 1;62(21):6246-54.
• [16] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [19] 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.
• [20] 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.
• [21] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [22] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.