Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT30UNI7)

• DOT Name: MLX-interacting protein (MLXIP)
• Synonyms: Class E basic helix-loop-helix protein 36; bHLHe36; Transcriptional activator MondoA
• Gene Name: MLXIP
• Related Disease:
  Congenital anomaly of kidney and urinary tract
  B-cell lymphoma
  B-cell neoplasm
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Cardiomyopathy
  Cervical cancer
  Cervical carcinoma
  Charcot-Marie-Tooth disease type 1A
  Clear cell renal carcinoma
  Dengue
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Euthyroid goiter
  Ewing sarcoma
  Follicular lymphoma
  Gout
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  High blood pressure
  Huntington disease
  leukaemia
  Liver cirrhosis
  Neoplasm
  Non-alcoholic fatty liver disease
  Non-small-cell lung cancer
  Pancreatic cancer
  Plasma cell myeloma
  Prostate cancer
  Prostate carcinoma
  Renal cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Vascular disease
  Advanced cancer
  Chronic hepatitis B virus infection
  Chronic obstructive pulmonary disease
  Lung cancer
  Lung carcinoma
  Obesity
  Osteoarthritis
  Small lymphocytic lymphoma
  OPTN-related open angle glaucoma
  Erectile dysfunction
  Hereditary breast carcinoma
  Metastatic malignant neoplasm
  Non-insulin dependent diabetes
• UniProt ID: MLXIP_HUMAN
• Pfam ID: PF00010
• Sequence:
  MAADVFMCSPRRPRSRGRQVLLKPQVSEDDDDSDTDEPSPPPASGAATPARAHASAAPPP
  PRAGPGREEPPRRQQIIHSGHFMVSSPHREHPPKKGYDFDTVNKQTCQTYSFGKTSSCHL
  SIDASLTKLFECMTLAYSGKLVSPKWKNFKGLKLQWRDKIRLNNAIWRAWYMQYLEKRKN
  PVCHFVTPLDGSVDVDEHRRPEAITTEGKYWKSRIEIVIREYHKWRTYFKKRLQQHKDED
  LSSLVQDDDMLYWHKHGDGWKTPVPMEEDPLLDTDMLMSEFSDTLFSTLSSHQPVAWPNP
  REIAHLGNADMIQPGLIPLQPNLDFMDTFEPFQDLFSSSRSIFGSMLPASASAPVPDPNN
  PPAQESILPTTALPTVSLPDSLIAPPTAPSLAHMDEQGCEHTSRTEDPFIQPTDFGPSEP
  PLSVPQPFLPVFTMPLLSPSPAPPPISPVLPLVPPPATALNPPAPPTFHQPQKFAGVNKA
  PSVITHTASATLTHDAPATTFSQSQGLVITTHHPAPSAAPCGLALSPVTRPPQPRLTFVH
  PKPVSLTGGRPKQPHKIVPAPKPEPVSLVLKNARIAPAAFSGQPQAVIMTSGPLKREGML
  ASTVSQSNVVIAPAAIARAPGVPEFHSSILVTDLGHGTSSPPAPVSRLFPSTAQDPLGKG
  EQVPLHGGSPQVTVTGPSRDCPNSGQASPCASEQSPSPQSPQNNCSGKSDPKNVAALKNR
  QMKHISAEQKRRFNIKMCFDMLNSLISNNSKLTSHAITLQKTVEYITKLQQERGQMQEEA
  RRLREEIEELNATIISCQQLLPATGVPVTRRQFDHMKDMFDEYVKTRTLQNWKFWIFSII
  IKPLFESFKGMVSTSSLEELHRTALSWLDQHCSLPILRPMVLSTLRQLSTSTSILTDPAQ
  LPEQASKAVTRIGKRLGES
• Function: Binds DNA as a heterodimer with MLX and activates transcription. Binds to the canonical E box sequence 5'-CACGTG-3'. Plays a role in transcriptional activation of glycolytic target genes. Involved in glucose-responsive gene regulation.
• Tissue Specificity: Widely expressed in adult tissues. Most abundant in skeletal muscle.
• KEGG Pathway:
  Insulin resistance (hsa04931)
  Non-alcoholic fatty liver disease (hsa04932)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital anomaly of kidney and urinary tract	DIS84IVH	Definitive	Altered Expression	[1]
B-cell lymphoma	DISIH1YQ	Strong	Altered Expression	[2]
B-cell neoplasm	DISVY326	Strong	Genetic Variation	[3]
Bladder cancer	DISUHNM0	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[5]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[6]
Cervical cancer	DISFSHPF	Strong	Genetic Variation	[7]
Cervical carcinoma	DIST4S00	Strong	Genetic Variation	[7]
Charcot-Marie-Tooth disease type 1A	DISSRZG7	Strong	Genetic Variation	[8]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[9]
Dengue	DISKH221	Strong	Altered Expression	[10]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[11]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[12]
Euthyroid goiter	DISLRPYJ	Strong	Biomarker	[13]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[14]
Follicular lymphoma	DISVEUR6	Strong	Altered Expression	[2]
Gout	DISHC0U7	Strong	Genetic Variation	[15]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[16]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[17]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[18]
Huntington disease	DISQPLA4	Strong	Biomarker	[19]
leukaemia	DISS7D1V	Strong	Genetic Variation	[20]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[21]
Neoplasm	DISZKGEW	Strong	Biomarker	[22]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[23]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[24]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[25]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Biomarker	[26]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[26]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[9]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[4]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[4]
Vascular disease	DISVS67S	Strong	Genetic Variation	[18]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[27]
Chronic hepatitis B virus infection	DISHL4NT	moderate	Genetic Variation	[28]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Genetic Variation	[29]
Lung cancer	DISCM4YA	moderate	Altered Expression	[30]
Lung carcinoma	DISTR26C	moderate	Altered Expression	[30]
Obesity	DIS47Y1K	moderate	Biomarker	[31]
Osteoarthritis	DIS05URM	moderate	Biomarker	[32]
Small lymphocytic lymphoma	DIS30POX	moderate	Altered Expression	[33]
OPTN-related open angle glaucoma	DISDR98A	Disputed	Genetic Variation	[34]
Erectile dysfunction	DISD8MTH	Limited	Biomarker	[35]
Hereditary breast carcinoma	DISAEZT5	Limited	Genetic Variation	[36]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[37]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[38]

10 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 MLX-interacting protein (MLXIP).	[39]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of MLX-interacting protein (MLXIP).	[40]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of MLX-interacting protein (MLXIP).	[41]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of MLX-interacting protein (MLXIP).	[42]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of MLX-interacting protein (MLXIP).	[43]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of MLX-interacting protein (MLXIP).	[44]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of MLX-interacting protein (MLXIP).	[45]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of MLX-interacting protein (MLXIP).	[46]
Menadione	DMSJDTY	Approved	Menadione affects the expression of MLX-interacting protein (MLXIP).	[47]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of MLX-interacting protein (MLXIP).	[48]

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 decreases the methylation of MLX-interacting protein (MLXIP).	[49]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
D-glucose	DMMG2TO	Investigative	D-glucose affects the localization of MLX-interacting protein (MLXIP).	[50]

References

• [1] Transcriptome-wide based identification of miRs in congenital anomalies of the kidney and urinary tract (CAKUT) in children: the significant upregulation of tissue miR-144 expression.J Transl Med. 2016 Jun 30;14(1):193. doi: 10.1186/s12967-016-0955-0.
• [2] Network analysis of microRNAs, genes and their regulation in diffuse and follicular B-cell lymphomas.Oncotarget. 2018 Jan 5;9(8):7928-7941. doi: 10.18632/oncotarget.23974. eCollection 2018 Jan 30.
• [3] Expression of hsa-MIR-204, RUNX2, PPAR, and BCL2 in Bone Marrow Derived Mesenchymal Stem Cells from Multiple Myeloma Patients and Normal Individuals.Cell J. 2017 Spring;19(Suppl 1):27-36. doi: 10.22074/cellj.2017.4480. Epub 2017 May 17.
• [4] MicroRNA-101 inhibits cell migration and invasion in bladder cancer via targeting FZD4.Exp Ther Med. 2019 Feb;17(2):1476-1485. doi: 10.3892/etm.2018.7084. Epub 2018 Dec 11.
• [5] Differential Expression of MicroRNAs in Breast Cancers from Four Different Ethnicities.Pathobiology. 2018;85(4):220-226. doi: 10.1159/000488456. Epub 2018 May 23.
• [6] Elucidation of transcriptome-wide microRNA binding sites in human cardiac tissues by Ago2 HITS-CLIP. Nucleic Acids Res. 2016 Sep 6;44(15):7120-31.
• [7] GRSF1-mediated MIR-G-1 promotes malignant behavior and nuclear autophagy by directly upregulating TMED5 and LMNB1 in cervical cancer cells.Autophagy. 2019 Apr;15(4):668-685. doi: 10.1080/15548627.2018.1539590. Epub 2018 Nov 5.
• [8] Association of miR-149 polymorphism with onset age and severity in Charcot-Marie-Tooth disease type 1A.Neuromuscul Disord. 2018 Jun;28(6):502-507. doi: 10.1016/j.nmd.2018.04.002. Epub 2018 Apr 11.
• [9] Linkage of microRNA and proteome-based profiling data sets: a perspective for the priorization of candidate biomarkers in renal cell carcinoma?.J Proteome Res. 2011 Jan 7;10(1):191-9. doi: 10.1021/pr1011137.
• [10] Dengue virus in Aedes aegypti and Aedes albopictus in urban areas in the state of Rio Grande do Norte, Brazil: Importance of virological and entomological surveillance.PLoS One. 2018 Mar 13;13(3):e0194108. doi: 10.1371/journal.pone.0194108. eCollection 2018.
• [11] MIR-92 stimulates VEGF by inhibiting von Hippel-Lindau gene product in epithelial ovarian cancer.J Biol Regul Homeost Agents. 2017 Jul-Sep,;31(3):615-624.
• [12] Genetic variation in miR-100 rs1834306 is associated with decreased risk for esophageal squamous cell carcinoma in Kazakh patients in northwest China.Int J Clin Exp Pathol. 2015 Jun 1;8(6):7332-40. eCollection 2015.
• [13] The adaptation of TSH secretion to autonomy in non-toxic goiter may be based-on active regulation of set-point and sensitivity of central TSH-receptors, perhaps by the microRNA (MIR) gene.Med Hypotheses. 2006;67(3):588-91. doi: 10.1016/j.mehy.2005.12.049. Epub 2006 May 5.
• [14] miR-185 suppresses progression of Ewing's sarcoma via inhibiting the PI3K/AKT and Wnt/-catenin pathways.Onco Targets Ther. 2018 Nov 9;11:7967-7977. doi: 10.2147/OTT.S167771. eCollection 2018.
• [15] Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.
• [16] Identification of an epigenetic profile classifier that is associated with survival in head and neck cancer.Cancer Res. 2012 Jun 1;72(11):2728-37. doi: 10.1158/0008-5472.CAN-11-4121-T. Epub 2012 Apr 16.
• [17] MicroRNA Gene Polymorphisms in Evaluating Therapeutic Efficacy After Transcatheter Arterial Chemoembolization for Primary Hepatocellular Carcinoma.Genet Test Mol Biomarkers. 2016 Oct;20(10):579-586. doi: 10.1089/gtmb.2016.0073. Epub 2016 Aug 15.
• [18] Associations of MicroRNA Polymorphisms (miR-146a, miR-196a2, and miR-499) with the Risk of Hypertension in the Korean Population.Genet Test Mol Biomarkers. 2016 Aug;20(8):420-6. doi: 10.1089/gtmb.2016.0039. Epub 2016 Jul 5.
• [19] Hsa-miR-34b is a plasma-stable microRNA that is elevated in pre-manifest Huntington's disease.Hum Mol Genet. 2011 Jun 1;20(11):2225-37. doi: 10.1093/hmg/ddr111. Epub 2011 Mar 19.
• [20] MicroRNA 146a Polymorphisms and Expression in Indian Children with Acute Lymphoblastic Leukemia.Lab Med. 2019 Jul 16;50(3):249-253. doi: 10.1093/labmed/lmy074.
• [21] Mid-infrared spectroscopy of serum, a promising non-invasive method to assess prognosis in patients with ascites and cirrhosis.PLoS One. 2017 Oct 11;12(10):e0185997. doi: 10.1371/journal.pone.0185997. eCollection 2017.
• [22] Overexpression of miR-199a-5p decreases esophageal cancer cell proliferation through repression of mitogen-activated protein kinase kinase kinase-11 (MAP3K11).Oncotarget. 2016 Feb 23;7(8):8756-70. doi: 10.18632/oncotarget.6752.
• [23] miRNA-132 induces hepatic steatosis and hyperlipidaemia by synergistic multitarget suppression.Gut. 2018 Jun;67(6):1124-1134. doi: 10.1136/gutjnl-2016-312869. Epub 2017 Apr 5.
• [24] Axl-Targeted Delivery of the Oncosuppressor miR-137 in Non-small-Cell Lung Cancer.Mol Ther Nucleic Acids. 2019 Sep 6;17:256-263. doi: 10.1016/j.omtn.2019.06.002. Epub 2019 Jun 13.
• [25] Garcinol sensitizes human pancreatic adenocarcinoma cells to gemcitabine in association with microRNA signatures.Mol Nutr Food Res. 2013 Feb;57(2):235-48. doi: 10.1002/mnfr.201200297. Epub 2013 Jan 7.
• [26] Methylation and MicroRNA Profiling to Understand Racial Disparities of Prostate Cancer.Methods Mol Biol. 2018;1856:255-267. doi: 10.1007/978-1-4939-8751-1_15.
• [27] Applications of mid-infrared spectroscopy in the clinical laboratory setting.Crit Rev Clin Lab Sci. 2018 Jan;55(1):1-20. doi: 10.1080/10408363.2017.1414142. Epub 2017 Dec 14.
• [28] Association of a variant in MIR 196A2 with susceptibility to hepatocellular carcinoma in male Chinese patients with chronic hepatitis B virus infection.Hum Immunol. 2010 Jun;71(6):621-6. doi: 10.1016/j.humimm.2010.02.017. Epub 2010 Mar 12.
• [29] Association of MicroRNA-196a2 Variant with Response to Short-Acting 2-Agonist in COPD: An Egyptian Pilot Study.PLoS One. 2016 Apr 4;11(4):e0152834. doi: 10.1371/journal.pone.0152834. eCollection 2016.
• [30] MicroRNA-125b may function as an oncogene in lung cancer cells.Mol Med Rep. 2015 May;11(5):3880-7. doi: 10.3892/mmr.2014.3142. Epub 2014 Dec 31.
• [31] The gut microbiota regulates white adipose tissue inflammation and obesity via a family of microRNAs.Sci Transl Med. 2019 Jun 12;11(496):eaav1892. doi: 10.1126/scitranslmed.aav1892.
• [32] The complex landscape of microRNAs in articular cartilage: biology, pathology, and therapeutic targets.JCI Insight. 2018 Sep 6;3(17):e121630. doi: 10.1172/jci.insight.121630. eCollection 2018 Sep 6.
• [33] Signal transducer and activator of transcription (STAT)-3 regulates microRNA gene expression in chronic lymphocytic leukemia cells.Mol Cancer. 2013 Jun 1;12:50. doi: 10.1186/1476-4598-12-50.
• [34] A Common Variant in MIR182 Is Associated With Primary Open-Angle Glaucoma in the NEIGHBORHOOD Consortium.Invest Ophthalmol Vis Sci. 2016 Aug 1;57(10):4528-4535. doi: 10.1167/iovs.16-19688.
• [35] The Changes of MicroRNA Expression in the Corpus Cavernosum of a Rat Model With Cavernous Nerve Injury.J Sex Med. 2018 Jul;15(7):958-965. doi: 10.1016/j.jsxm.2018.05.006.
• [36] Mutation screening of MIR146A/B and BRCA1/2 3'-UTRs in the GENESIS study.Eur J Hum Genet. 2016 Aug;24(9):1324-9. doi: 10.1038/ejhg.2015.284. Epub 2016 Jan 20.
• [37] Combined Effect of Metastasis-Related MicroRNA, miR-34 and miR-124 Family, Methylation on Prognosis of Non-Small-Cell Lung Cancer.Clin Lung Cancer. 2017 Jan;18(1):e13-e20. doi: 10.1016/j.cllc.2016.06.005. Epub 2016 Jun 23.
• [38] MicroRNA genetic variations: association with type 2 diabetes.Acta Diabetol. 2013 Dec;50(6):867-72. doi: 10.1007/s00592-013-0469-7. Epub 2013 Mar 27.
• [39] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [40] 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.
• [41] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [42] 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.
• [43] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [44] 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.
• [45] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [46] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [47] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [48] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [49] 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.
• [50] NF-B p65 regulates hepatic lipogenesis by promoting nuclear entry of ChREBP in response to a high carbohydrate diet. J Biol Chem. 2021 Jan-Jun;296:100714. doi: 10.1016/j.jbc.2021.100714. Epub 2021 Apr 27.