Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0LUIRG)

• DOT Name: Melanoregulin (MREG)
• Synonyms: Dilute suppressor protein homolog
• Gene Name: MREG
• Related Disease:
  Alcohol dependence
  Alcohol-induced disorders
  Alcohol-related disorders
  Hantavirus infection
  X-linked recessive ocular albinism
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
• UniProt ID: MREG_HUMAN
• Pfam ID: PF15812
• Sequence:
  MGLRDWLRTVCCCCGCECLEERALPEKEPLVSDNNPYSSFGATLVRDDEKNLWSMPHDVS
  HTEADDDRTLYNLIVIRNQQAKDSEEWQKLNYDIHTLRQVRREVRNRWKCILEDLGFQKE
  ADSLLSVTKLSTISDSKNTRKAREMLLKLAEETNIFPTSWELSERYLFVVDRLIALDAAE
  EFFKLARRTYPKKPGVPCLADGQKELHYLPFPSP
• Function: Probably functions as a cargo-recognition protein that couples cytoplasmic vesicles to the transport machinery. Plays a role in hair pigmentation, a process that involves shedding of melanosome-containing vesicles from melanocytes, followed by phagocytosis of the melanosome-containing vesicles by keratinocytes. Functions on melanosomes as receptor for RILP and the complex formed by RILP and DCTN1, and thereby contributes to retrograde melanosome transport from the cell periphery to the center. Overexpression causes accumulation of late endosomes and/or lysosomes at the microtubule organising center (MTOC) at the center of the cell. Probably binds cholesterol and requires the presence of cholesterol in membranes to function in microtubule-mediated retrograde organelle transport. Binds phosphatidylinositol 3-phosphate, phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate and phosphatidylinositol 3,5-bisphosphate, but not phosphatidylinositol 3,4-bisphosphate or phosphatidylinositol 4,5-bisphosphate. Required for normal phagosome clearing and normal activation of lysosomal enzymes in lysosomes from retinal pigment epithelium cells. Required for normal degradation of the lipofuscin component N-retinylidene-N-retinylethanolamine (A2E) in the eye. May function in membrane fusion and regulate the biogenesis of disk membranes of photoreceptor rod cells.
• Tissue Specificity: Expressed in photoreceptor cells (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[1]
Alcohol-induced disorders	DIS3SFYT	moderate	Genetic Variation	[2]
Alcohol-related disorders	DIS3K4KK	moderate	Genetic Variation	[2]
Hantavirus infection	DISZFTMH	moderate	Biomarker	[3]
X-linked recessive ocular albinism	DISI9S32	moderate	Genetic Variation	[3]
Thyroid cancer	DIS3VLDH	Limited	Biomarker	[4]
Thyroid gland carcinoma	DISMNGZ0	Limited	Biomarker	[4]
Thyroid tumor	DISLVKMD	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Melanoregulin (MREG).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Melanoregulin (MREG).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Melanoregulin (MREG).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Melanoregulin (MREG).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Melanoregulin (MREG).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Melanoregulin (MREG).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Melanoregulin (MREG).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Melanoregulin (MREG).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Melanoregulin (MREG).	[13]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Melanoregulin (MREG).	[14]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Melanoregulin (MREG).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Melanoregulin (MREG).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Melanoregulin (MREG).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Melanoregulin (MREG).	[18]

References

• [1] Genome-wide association discoveries of alcohol dependence.Am J Addict. 2014 Nov-Dec;23(6):526-39. doi: 10.1111/j.1521-0391.2014.12147.x.
• [2] Genome-wide association study of alcohol dependence.Arch Gen Psychiatry. 2009 Jul;66(7):773-84. doi: 10.1001/archgenpsychiatry.2009.83.
• [3] Melanoregulin, product of the dsu locus, links the BLOC-pathway and OA1 in organelle biogenesis.PLoS One. 2012;7(9):e42446. doi: 10.1371/journal.pone.0042446. Epub 2012 Sep 11.
• [4] MREG suppresses thyroid cancer cell invasion and proliferation by inhibiting Akt-mTOR signaling.Biochem Biophys Res Commun. 2017 Sep 9;491(1):72-78. doi: 10.1016/j.bbrc.2017.07.044. Epub 2017 Jul 8.
• [5] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [11] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [12] 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.
• [13] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [14] 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.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.