Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEBLU3E)

• DOT Name: Lens fiber major intrinsic protein (MIP)
• Synonyms: Aquaporin-0; MIP26; MP26
• Gene Name: MIP
• Related Disease:
  Cataract 15 multiple types
  Cataract 20 multiple types
  Adult glioblastoma
  Advanced cancer
  Carcinoma
  Cataract
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Congestive heart failure
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Hypercalcaemia
  Kaposi sarcoma
  Legionnaires' disease
  Leukemia
  Lung adenocarcinoma
  Metastatic malignant neoplasm
  Multiple sclerosis
  Neoplasm
  Osteoarthritis
  Parkinson disease
  Plasma cell myeloma
  Pneumonitis
  Respiratory syncytial virus infection
  Rheumatoid arthritis
  Tuberculosis
  Ulcerative colitis
  Cataract 5 multiple types
  Hepatitis C virus infection
  HIV infectious disease
  Pulmonary fibrosis
  Renal cell carcinoma
  Cerulean cataract
  Early-onset lamellar cataract
  Early-onset nuclear cataract
  Early-onset posterior polar cataract
  Early-onset sutural cataract
  Total early-onset cataract
  Acute myelogenous leukaemia
  Bone disease
  Breast cancer
  Breast carcinoma
  Coronary heart disease
  Inflammatory bowel disease
  Lung cancer
  Lung carcinoma
  Obesity
  Type-1/2 diabetes
• UniProt ID: MIP_HUMAN
• Pfam ID: PF00230
• Sequence:
  MWELRSASFWRAIFAEFFATLFYVFFGLGSSLRWAPGPLHVLQVAMAFGLALATLVQSVG
  HISGAHVNPAVTFAFLVGSQMSLLRAFCYMAAQLLGAVAGAAVLYSVTPPAVRGNLALNT
  LHPAVSVGQATTVEIFLTLQFVLCIFATYDERRNGQLGSVALAVGFSLALGHLFGMYYTG
  AGMNPARSFAPAILTGNFTNHWVYWVGPIIGGGLGSLLYDFLLFPRLKSISERLSVLKGA
  KPDVSNGQPEVTGEPVELNTQAL
• Function: Water channel. Channel activity is down-regulated by CALM when cytoplasmic Ca(2+) levels are increased. May be responsible for regulating the osmolarity of the lens. Interactions between homotetramers from adjoining membranes may stabilize cell junctions in the eye lens core. Plays a role in cell-to-cell adhesion and facilitates gap junction coupling.
• Tissue Specificity: Expressed in the cortex and nucleus of the retina lens (at protein level) . Major component of lens fiber gap junctions .
• Reactome Pathway: Passive transport by Aquaporins (R-HSA-432047)

Molecular Interaction Atlas (MIA) of This DOT

50 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cataract 15 multiple types	DISPYZV4	Definitive	Autosomal dominant	[1]
Cataract 20 multiple types	DISN0IHS	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[4]
Cataract	DISUD7SL	Strong	Biomarker	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[3]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[9]
Hypercalcaemia	DISKQ2K7	Strong	Biomarker	[10]
Kaposi sarcoma	DISC1H1Z	Strong	Biomarker	[11]
Legionnaires' disease	DIS8V4GQ	Strong	Genetic Variation	[12]
Leukemia	DISNAKFL	Strong	Biomarker	[13]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[14]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[15]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[16]
Neoplasm	DISZKGEW	Strong	Biomarker	[17]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[18]
Parkinson disease	DISQVHKL	Strong	Biomarker	[19]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[20]
Pneumonitis	DIS88E0K	Strong	Biomarker	[21]
Respiratory syncytial virus infection	DIS7FWHY	Strong	Biomarker	[22]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[23]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[24]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[25]
Cataract 5 multiple types	DIS4AZEB	moderate	Genetic Variation	[26]
Hepatitis C virus infection	DISQ0M8R	moderate	Genetic Variation	[27]
HIV infectious disease	DISO97HC	moderate	Biomarker	[27]
Pulmonary fibrosis	DISQKVLA	moderate	Altered Expression	[28]
Renal cell carcinoma	DISQZ2X8	moderate	Biomarker	[6]
Cerulean cataract	DIS5D1OI	Supportive	Autosomal dominant	[29]
Early-onset lamellar cataract	DISR7WXX	Supportive	Autosomal dominant	[26]
Early-onset nuclear cataract	DISGIHUY	Supportive	Autosomal dominant	[30]
Early-onset posterior polar cataract	DISJFK9W	Supportive	Autosomal dominant	[31]
Early-onset sutural cataract	DISKFS14	Supportive	Autosomal dominant	[32]
Total early-onset cataract	DISACMEZ	Supportive	Autosomal dominant	[33]
Acute myelogenous leukaemia	DISCSPTN	Limited	Altered Expression	[34]
Bone disease	DISE1F82	Limited	Biomarker	[35]
Breast cancer	DIS7DPX1	Limited	Biomarker	[36]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[36]
Coronary heart disease	DIS5OIP1	Limited	Altered Expression	[37]
Inflammatory bowel disease	DISGN23E	Limited	Altered Expression	[38]
Lung cancer	DISCM4YA	Limited	Biomarker	[39]
Lung carcinoma	DISTR26C	Limited	Biomarker	[39]
Obesity	DIS47Y1K	Limited	Biomarker	[40]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[41]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Lens fiber major intrinsic protein (MIP).	[42]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Lens fiber major intrinsic protein (MIP).	[45]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Lens fiber major intrinsic protein (MIP).	[43]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Lens fiber major intrinsic protein (MIP).	[44]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Lens fiber major intrinsic protein (MIP).	[46]

References

• [1] Missense mutations in MIP underlie autosomal dominant 'polymorphic' and lamellar cataracts linked to 12q. Nat Genet. 2000 May;25(1):15-7. doi: 10.1038/75538.
• [2] Morphine exacerbates HIV-1 viral protein gp120 induced modulation of chemokine gene expression in U373 astrocytoma cells.Curr HIV Res. 2005 Jul;3(3):277-88. doi: 10.2174/1570162054368048.
• [3] Macrophage inflammatory protein-1alpha C-C chemokine in parapneumonic pleural effusions.J Lab Clin Med. 1998 Sep;132(3):202-9. doi: 10.1016/s0022-2143(98)90169-x.
• [4] Choroid plexus carcinomas are characterized by complex chromosomal alterations related to patient age and prognosis.Genes Chromosomes Cancer. 2014 May;53(5):373-80. doi: 10.1002/gcc.22148. Epub 2014 Jan 30.
• [5] Deletion of Seventeen Amino Acids at the C-Terminal End of Aquaporin 0 Causes Distortion Aberration and Cataract in the Lenses of AQP0C/C Mice.Invest Ophthalmol Vis Sci. 2019 Mar 1;60(4):858-867. doi: 10.1167/iovs.18-26378.
• [6] The Lim1 oncogene as a new therapeutic target for metastatic human renal cell carcinoma.Oncogene. 2019 Jan;38(1):60-72. doi: 10.1038/s41388-018-0413-y. Epub 2018 Aug 3.
• [7] Expression profiling and interferon-beta regulation of liver metastases in colorectal cancer cells.Clin Exp Metastasis. 2002;19(6):541-50. doi: 10.1023/a:1020325327461.
• [8] Inflammatory Molecule, PSGL-1, Deficiency Activates Macrophages to Promote Colorectal Cancer Growth through NFB Signaling.Mol Cancer Res. 2017 Apr;15(4):467-477. doi: 10.1158/1541-7786.MCR-16-0309. Epub 2017 Jan 20.
• [9] Finding a novel interacting protein of the hepatic carcinoma related gene MIP: NF-B essential modulator (NEMO).Oncol Rep. 2011 Jan;25(1):231-5.
• [10] Over-expression of CCL3 MIP-1alpha in a blastoid mantle cell lymphoma with hypercalcemia.Eur J Haematol. 2010 May;84(5):448-52. doi: 10.1111/j.1600-0609.2009.01405.x. Epub 2010 Dec 24.
• [11] Chemokine receptors: interaction with HIV-1 and viral-encoded chemokines.Pharm Acta Helv. 2000 Mar;74(2-3):305-12. doi: 10.1016/s0031-6865(99)00040-0.
• [12] Application of Legionella pneumophila-specific quantitative real-time PCR combined with direct amplification and sequence-based typing in the diagnosis and epidemiological investigation of Legionnaires' disease.Eur J Clin Microbiol Infect Dis. 2012 Aug;31(8):2017-28. doi: 10.1007/s10096-011-1535-0. Epub 2012 Jan 26.
• [13] Transcriptional regulation of the human MIP-1alpha promoter by RUNX1 and MOZ.Nucleic Acids Res. 2003 Jun 1;31(11):2735-44. doi: 10.1093/nar/gkg401.
• [14] Comprehensive Profiling of Gene Copy Number Alterations Predicts Patient Prognosis in Resected Stages I-III Lung Adenocarcinoma.Front Oncol. 2019 Aug 6;9:556. doi: 10.3389/fonc.2019.00556. eCollection 2019.
• [15] Macrophage inflammatory protein-3alpha is a novel serum marker for nasopharyngeal carcinoma detection and prediction of treatment outcomes.Clin Cancer Res. 2008 Nov 1;14(21):6979-87. doi: 10.1158/1078-0432.CCR-08-0090.
• [16] A Review of Various Antioxidant Compounds and their Potential Utility as Complementary Therapy in Multiple Sclerosis.Nutrients. 2019 Jul 5;11(7):1528. doi: 10.3390/nu11071528.
• [17] Chemical Antibody Mimics Inhibit Cadherin-Mediated Cell-Cell Adhesion: A Promising Strategy for Cancer Therapy.Angew Chem Int Ed Engl. 2020 Feb 10;59(7):2816-2822. doi: 10.1002/anie.201910373. Epub 2019 Nov 27.
• [18] Depletion of aquaporin 1 decreased ADAMTS? expression in human chondrocytes.Mol Med Rep. 2018 Apr;17(4):4874-4882. doi: 10.3892/mmr.2018.8545. Epub 2018 Feb 2.
• [19] Respiratory muscle strength and lung function in the stages of Parkinson's disease.J Bras Pneumol. 2019 Sep 30;45(6):e20180148. doi: 10.1590/1806-3713/e20180148. eCollection 2019.
• [20] Chemokine-idiotype fusion DNA vaccines are potentiated by bivalency and xenogeneic sequences.Blood. 2007 Sep 15;110(6):1797-805. doi: 10.1182/blood-2006-06-032938. Epub 2007 May 31.
• [21] Matrix metalloproteinase-8 inactivates macrophage inflammatory protein-1 alpha to reduce acute lung inflammation and injury in mice.J Immunol. 2010 Feb 1;184(3):1575-88. doi: 10.4049/jimmunol.0900290. Epub 2009 Dec 30.
• [22] Peripheral blood mononuclear cells from infants hospitalized because of respiratory syncytial virus infection express T helper-1 and T helper-2 cytokines and CC chemokine messenger RNA.J Infect Dis. 2002 May 15;185(10):1388-94. doi: 10.1086/340505. Epub 2002 Apr 30.
• [23] Regulation of CCR5 expression and MIP-1alpha production in CD4+ T cells from patients with rheumatoid arthritis.Clin Exp Immunol. 2003 May;132(2):371-8. doi: 10.1046/j.1365-2249.2003.02126.x.
• [24] Association between RANTES functional polymorphisms and tuberculosis in Hong Kong Chinese.Genes Immun. 2007 Sep;8(6):475-9. doi: 10.1038/sj.gene.6364412. Epub 2007 Jul 12.
• [25] Polymorphisms of the macrophage inflammatory protein 1 alpha and ApoE genes are associated with ulcerative colitis.Int J Colorectal Dis. 2009 Jan;24(1):13-7. doi: 10.1007/s00384-008-0575-0. Epub 2008 Sep 2.
• [26] An MIP/AQP0 mutation with impaired trafficking and function underlies an autosomal dominant congenital lamellar cataract. Exp Eye Res. 2013 May;110:136-41. doi: 10.1016/j.exer.2012.10.010. Epub 2012 Oct 29.
• [27] HCV adaptation to HIV coinfection.Infect Genet Evol. 2018 Nov;65:216-225. doi: 10.1016/j.meegid.2018.07.039. Epub 2018 Jul 31.
• [28] Augmented production of chemokines (monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta) in patients with systemic sclerosis: MCP-1 and MIP-1alpha may be involved in the development of pulmonary fibrosis.Clin Exp Immunol. 1999 Jul;117(1):159-65. doi: 10.1046/j.1365-2249.1999.00929.x.
• [29] Cerulean cataract mapped to 12q13 and associated with a novel initiation codon mutation in MIP. Mol Vis. 2011;17:2049-55. Epub 2011 Jul 26.
• [30] A novel mutation in MIP associated with congenital nuclear cataract in a Chinese family. Mol Vis. 2011 Jan 8;17:70-7.
• [31] A novel nonsense mutation in the MIP gene linked to congenital posterior polar cataracts in a Chinese family. PLoS One. 2015 Mar 24;10(3):e0119296. doi: 10.1371/journal.pone.0119296. eCollection 2015.
• [32] A novel mutation in the major intrinsic protein (MIP) associated with autosomal dominant congenital cataracts in a Chinese family. Mol Vis. 2010 Mar 25;16:534-9.
• [33] A novel mutation in major intrinsic protein of the lens gene (MIP) underlies autosomal dominant cataract in a Chinese family. Mol Vis. 2007 Sep 11;13:1651-6.
• [34] AML-1A and AML-1B regulation of MIP-1alpha expression in multiple myeloma.Blood. 2003 May 15;101(10):3778-83. doi: 10.1182/blood-2002-08-2641. Epub 2003 Jan 30.
• [35] Significance of macrophage inflammatory protein-1 alpha (MIP-1alpha) in multiple myeloma.Leuk Lymphoma. 2005 Dec;46(12):1699-707. doi: 10.1080/10428190500175049.
• [36] Abbreviated MRI Protocols for Detecting Breast Cancer in Women with Dense Breasts.Korean J Radiol. 2017 May-Jun;18(3):470-475. doi: 10.3348/kjr.2017.18.3.470. Epub 2017 Apr 3.
• [37] Serum amyloid A induction of cytokines in monocytes/macrophages and lymphocytes.Atherosclerosis. 2009 Dec;207(2):374-83. doi: 10.1016/j.atherosclerosis.2009.05.007. Epub 2009 May 21.
• [38] Colonic epithelial cells are a major site of macrophage inflammatory protein 3alpha (MIP-3alpha) production in normal colon and inflammatory bowel disease.Gut. 2002 Dec;51(6):818-26. doi: 10.1136/gut.51.6.818.
• [39] Characteristic analysis of pulmonary ground-glass lesions with the help of 64-slice CT technology.Eur Rev Med Pharmacol Sci. 2017 Jul;21(14):3212-3217.
• [40] MIP-1 Induction by Palmitate in the Human Monocytic Cells Implicates TLR4 Signaling Mechanism.Cell Physiol Biochem. 2019;52(2):212-224. doi: 10.33594/000000015. Epub 2019 Feb 28.
• [41] MANF Is Required for the Postnatal Expansion and Maintenance of Pancreatic -Cell Mass in Mice.Diabetes. 2019 Jan;68(1):66-80. doi: 10.2337/db17-1149. Epub 2018 Oct 10.
• [42] 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.
• [43] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [44] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [45] 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.
• [46] BET bromodomain protein inhibition is a therapeutic option for medulloblastoma. Oncotarget. 2013 Nov;4(11):2080-95.