Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7ADCXL)

• DOT Name: Melanophilin (MLPH)
• Synonyms: Exophilin-3; Slp homolog lacking C2 domains a; SlaC2-a; Synaptotagmin-like protein 2a
• Gene Name: MLPH
• Related Disease:
  Prostate cancer
  Prostate carcinoma
  Autism
  Griscelli syndrome
  Griscelli syndrome type 3
  Hypopigmentation of the skin
  Neoplasm
  Osteoporosis
  Meningioma
• UniProt ID: MELPH_HUMAN
• Pfam ID: PF02318 ; PF04698
• Sequence:
  MGKKLDLSKLTDEEAQHVLEVVQRDFDLRRKEEERLEALKGKIKKESSKRELLSDTAHLN
  ETHCARCLQPYQLLVNSKRQCLECGLFTCKSCGRVHPEEQGWICDPCHLARVVKIGSLEW
  YYEHVKARFKRFGSAKVIRSLHGRLQGGAGPELISEERSGDSDQTDEDGEPGSEAQAQAQ
  PFGSKKKRLLSVHDFDFEGDSDDSTQPQGHSLHLSSVPEARDSPQSLTDESCSEKAAPHK
  AEGLEEADTGASGCHSHPEEQPTSISPSRHGALAELCPPGGSHRMALGTAAALGSNVIRN
  EQLPLQYLADVDTSDEESIRAHVMASHHSKRRGRASSESQIFELNKHISAVECLLTYLEN
  TVVPPLAKGLGAGVRTEADVEEEALRRKLEELTSNVSDQETSSEEEEAKDEKAEPNRDKS
  VGPLPQADPEVGTAAHQTNRQEKSPQDPGDPVQYNRTTDEELSELEDRVAVTASEVQQAE
  SEVSDIESRIAALRAAGLTVKPSGKPRRKSNLPIFLPRVAGKLGKRPEDPNADPSSEAKA
  MAVPYLLRRKFSNSLKSQGKDDDSFDRKSVYRGSLTQRNPNARKGMASHTFAKPVVAHQS
• Function: Rab effector protein involved in melanosome transport. Serves as link between melanosome-bound RAB27A and the motor protein MYO5A.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Definitive	Genetic Variation	[1]
Prostate carcinoma	DISMJPLE	Definitive	Genetic Variation	[1]
Autism	DISV4V1Z	Strong	Genetic Variation	[2]
Griscelli syndrome	DISTHCOQ	Strong	Genetic Variation	[3]
Griscelli syndrome type 3	DISG4PY1	Strong	Autosomal recessive	[4]
Hypopigmentation of the skin	DIS39YKC	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Osteoporosis	DISF2JE0	Strong	Biomarker	[6]
Meningioma	DISPT4TG	moderate	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DTI-015	DMXZRW0	Approved	Melanophilin (MLPH) affects the response to substance of DTI-015.	[24]

17 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 Melanophilin (MLPH).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Melanophilin (MLPH).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Melanophilin (MLPH).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Melanophilin (MLPH).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Melanophilin (MLPH).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Melanophilin (MLPH).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Melanophilin (MLPH).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Melanophilin (MLPH).	[15]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Melanophilin (MLPH).	[16]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Melanophilin (MLPH).	[17]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Melanophilin (MLPH).	[18]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Melanophilin (MLPH).	[19]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Melanophilin (MLPH).	[20]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Melanophilin (MLPH).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Melanophilin (MLPH).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Melanophilin (MLPH).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Melanophilin (MLPH).	[23]

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 decreases the methylation of Melanophilin (MLPH).	[21]

References

• [1] Single-nucleotide polymorphism rs13426236 contributes to an increased prostate cancer risk via regulating MLPH splicing variant 4.Mol Carcinog. 2020 Jan;59(1):45-55. doi: 10.1002/mc.23127. Epub 2019 Oct 29.
• [2] Deletion 2q37.3 and autism: molecular cytogenetic mapping of the candidate region for autistic disorder.Genet Couns. 2004;15(3):293-301.
• [3] Cellular and clinical report of new Griscelli syndrome type III cases.Pigment Cell Melanoma Res. 2012 Jan;25(1):47-56. doi: 10.1111/j.1755-148X.2011.00901.x. Epub 2011 Oct 3.
• [4] Mutations in Mlph, encoding a member of the Rab effector family, cause the melanosome transport defects observed in leaden mice. Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10238-43. doi: 10.1073/pnas.181336698. Epub 2001 Aug 14.
• [5] Putative Prostate Cancer Risk SNP in an Androgen Receptor-Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites.Hum Mutat. 2016 Jan;37(1):52-64. doi: 10.1002/humu.22909. Epub 2015 Oct 19.
• [6] STRA6 as a possible candidate gene for pathogenesis of osteoporosis from RNAseq analysis of human mesenchymal stem cells.Mol Med Rep. 2017 Oct;16(4):4075-4081. doi: 10.3892/mmr.2017.7072. Epub 2017 Jul 21.
• [7] Microarray gene expression profiling in meningiomas: differential expression according to grade or histopathological subtype.Int J Oncol. 2009 Dec;35(6):1395-407. doi: 10.3892/ijo_00000457.
• [8] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [9] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [10] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [11] 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.
• [12] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [17] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [18] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [19] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [20] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [21] 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.
• [22] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [23] 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.
• [24] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.