Details of Drug Off-Target (DOT)

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

• DOT Name: MyoD family inhibitor domain-containing protein (MDFIC)
• Synonyms: I-mfa domain-containing protein; hIC
• Gene Name: MDFIC
• Related Disease:
  Advanced cancer
  Cardiac failure
  Congestive heart failure
  Crohn disease
  Inflammatory bowel disease
  Interstitial cystitis
  Language disorder
  Lymphatic malformation 12
  Neoplasm
  Obesity
  Overactive bladder
  Ulcerative colitis
  Cardiomyopathy
• UniProt ID: MDFIC_HUMAN
• Pfam ID: PF15316
• Sequence:
  MSGAGEALAPGPVGPQRVAEAGGGQLGSTAQGKCDKDNTEKDITQATNSHFTHGEMQDQS
  IWGNPSDGELIRTQPQRLPQLQTSAQVPSGEEIGKIKNGHTGLSNGNGIHHGAKHGSADN
  RKLSAPVSQKMHRKIQSSLSVNSDISKKSKVNAVFSQKTGSSPEDCCVHCILACLFCEFL
  TLCNIVLGQASCGICTSEACCCCCGDEMGDDCNCPCDMDCGIMDACCESSDCLEICMECC
  GICFPS
• Function: Required to control the activity of various transcription factors through their sequestration in the cytoplasm. Retains nuclear Zic proteins ZIC1, ZIC2 and ZIC3 in the cytoplasm and inhibits their transcriptional activation. Modulates the expression from both cellular and viral promoters. Down-regulates Tat-dependent transcription of the human immunodeficiency virus type 1 (HIV-1) LTR by interacting with HIV-1 Tat and Rev and impairing their nuclear import, probably by rendering the NLS domains inaccessible to importin-beta. Also stimulates activation of human T-cell leukemia virus type I (HTLV-I) LTR. Binds to the axin complex, resulting in an increase in the level of free beta-catenin. Affects axin regulation of the WNT and JNK signaling pathways. Has a role in the development of lymphatic vessel valves. It is required to promote lymphatic endothelial cell migration, in a process that involves down-regulation of integrin beta 1 activation and control of cell adhesion to the extracellular matrix.
• Tissue Specificity: Expressed in lymphatic tissues. Detected in the spleen, thymus, peripheral blood leukocytes as well as prostate, uterus and small intestine. Expressed in lymphatic endothelial cells .

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Cardiac failure	DISDC067	Strong	Biomarker	[2]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[2]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[3]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[3]
Interstitial cystitis	DIS7CAJA	Strong	Biomarker	[4]
Language disorder	DISTLKP7	Strong	Genetic Variation	[5]
Lymphatic malformation 12	DISZ6SY5	Strong	Autosomal recessive	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Obesity	DIS47Y1K	Strong	Biomarker	[8]
Overactive bladder	DISQR5TD	Strong	Biomarker	[4]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[3]
Cardiomyopathy	DISUPZRG	Disputed	Genetic Variation	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	MyoD family inhibitor domain-containing protein (MDFIC) affects the response to substance of Etoposide.	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of MyoD family inhibitor domain-containing protein (MDFIC).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of MyoD family inhibitor domain-containing protein (MDFIC).	[22]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of MyoD family inhibitor domain-containing protein (MDFIC).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of MyoD family inhibitor domain-containing protein (MDFIC).	[27]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of MyoD family inhibitor domain-containing protein (MDFIC).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of MyoD family inhibitor domain-containing protein (MDFIC).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of MyoD family inhibitor domain-containing protein (MDFIC).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of MyoD family inhibitor domain-containing protein (MDFIC).	[13]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of MyoD family inhibitor domain-containing protein (MDFIC).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of MyoD family inhibitor domain-containing protein (MDFIC).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of MyoD family inhibitor domain-containing protein (MDFIC).	[16]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of MyoD family inhibitor domain-containing protein (MDFIC).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of MyoD family inhibitor domain-containing protein (MDFIC).	[18]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of MyoD family inhibitor domain-containing protein (MDFIC).	[19]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of MyoD family inhibitor domain-containing protein (MDFIC).	[20]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of MyoD family inhibitor domain-containing protein (MDFIC).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of MyoD family inhibitor domain-containing protein (MDFIC).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of MyoD family inhibitor domain-containing protein (MDFIC).	[25]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of MyoD family inhibitor domain-containing protein (MDFIC).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of MyoD family inhibitor domain-containing protein (MDFIC).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of MyoD family inhibitor domain-containing protein (MDFIC).	[29]

References

• [1] A systematic review of integrative clinical trials for supportive care in pediatric oncology: a report from the International Society of Pediatric Oncology, T&CM collaborative.Support Care Cancer. 2018 Feb;26(2):375-391. doi: 10.1007/s00520-017-3908-0. Epub 2017 Oct 13.
• [2] Effect of 6 wk of high-intensity one-legged cycling on functional sympatholysis and ATP signaling in patients with heart failure.Am J Physiol Heart Circ Physiol. 2018 Mar 1;314(3):H616-H626. doi: 10.1152/ajpheart.00379.2017. Epub 2017 Nov 22.
• [3] Paediatric inflammatory bowel disease: review with a focus on practice in low- to middle-income countries.Paediatr Int Child Health. 2019 Feb;39(1):48-58. doi: 10.1080/20469047.2019.1575056.
• [4] Comparison of inflammatory urine markers in patients with interstitial cystitis and overactive bladder.Int Urogynecol J. 2018 Jul;29(7):961-966. doi: 10.1007/s00192-017-3547-5. Epub 2018 Jan 25.
• [5] Phenotype of FOXP2 haploinsufficiency in a mother and son.Am J Med Genet A. 2012 Jan;158A(1):174-81. doi: 10.1002/ajmg.a.34354. Epub 2011 Nov 21.
• [6] Pathogenic variants in MDFIC cause recessive central conducting lymphatic anomaly with lymphedema. Sci Transl Med. 2022 Mar 2;14(634):eabm4869. doi: 10.1126/scitranslmed.abm4869. Epub 2022 Mar 2.
• [7] I-mfa domain proteins specifically interact with HTLV-1 Tax and repress its transactivating functions.Virology. 2015 Dec;486:219-27. doi: 10.1016/j.virol.2015.09.020. Epub 2015 Oct 27.
• [8] Global nutrition 1990-2015: A shrinking hungry, and expanding fat world.PLoS One. 2018 Mar 27;13(3):e0194821. doi: 10.1371/journal.pone.0194821. eCollection 2018.
• [9] Postmortem diagnosis of left dominant arrhythmogenic cardiomyopathy: the importance of a multidisciplinary network for sudden death victims. "HIC mors gaudet succurere vitae".Cardiovasc Pathol. 2020 Jan-Feb;44:107157. doi: 10.1016/j.carpath.2019.107157. Epub 2019 Oct 10.
• [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] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [12] 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.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [15] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [16] 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.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] 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.
• [19] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [20] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [21] Comparative gene expression analysis of a chronic myelogenous leukemia cell line resistant to cyclophosphamide using oligonucleotide arrays and response to tyrosine kinase inhibitors. Leuk Res. 2007 Nov;31(11):1511-20.
• [22] 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.
• [23] 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.
• [24] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [25] 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.
• [26] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [27] 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.
• [28] 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.
• [29] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [30] 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.
• [31] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.