Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV9RZ53)

• DOT Name: Interferon-induced 35 kDa protein (IFI35)
• Synonyms: IFP 35; Ifi-35
• Gene Name: IFI35
• Related Disease:
  Astrocytoma
  Chronic kidney disease
  Influenza
  Lupus nephritis
  Rheumatoid arthritis
• UniProt ID: IN35_HUMAN
• Pfam ID: PF07334 ; PF07292
• Sequence:
  MSAPLDAALHALQEEQARLKMRLWDLQQLRKELGDSPKDKVPFSVPKIPLVFRGHTQQDP
  EVPKSLVSNLRIHCPLLAGSALITFDDPKVAEQVLQQKEHTINMEECRLRVQVQPLELPM
  VTTIQMSSQLSGRRVLVTGFPASLRLSEEELLDKLEIFFGKTRNGGGDVDVRELLPGSVM
  LGFARDGVAQRLCQIGQFTVPLGGQQVPLRVSPYVNGEIQKAEIRSQPVPRSVLVLNIPD
  ILDGPELHDVLEIHFQKPTRGGGEVEALTVVPQGQQGLAVFTSESG
• Function: Acts as a signaling pathway regulator involved in innate immune system response. In response to interferon IFN-alpha, associates in a complex with signaling pathway regulator NMI to regulate immune response; the complex formation prevents proteasome-mediated degradation of IFI35 and correlates with IFI35 dephosphorylation. In complex with NMI, inhibits virus-triggered type I interferon/IFN-beta production. In complex with NMI, negatively regulates nuclear factor NF-kappa-B signaling by inhibiting the nuclear translocation, activation and transcription of the NF-kappa-B subunit p65/RELA, resulting in the inhibition of endothelial cell proliferation, migration and re-endothelialization of injured arteries. Beside its role as an intracellular signaling pathway regulator, also functions extracellularly as damage-associated molecular patterns (DAMPs) to promote inflammation when actively released by macrophage to the extracellular space during cell injury and pathogen invasion. Macrophage-secreted IFI35 activates NF-kappa-B signaling in adjacent macrophages through Toll-like receptor 4/TLR4 activation, thereby inducing NF-kappa-B translocation from the cytoplasm into the nucleus which promotes the release of pro-inflammatory cytokines.
• Tissue Specificity: Expressed in a wide range of cell types, including fibroblasts, macrophages, and epithelial cells.
• Reactome Pathway: Interferon alpha/beta signaling (R-HSA-909733)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Astrocytoma	DISL3V18	Strong	Altered Expression	[1]
Chronic kidney disease	DISW82R7	Strong	Altered Expression	[2]
Influenza	DIS3PNU3	Strong	Biomarker	[3]
Lupus nephritis	DISCVGPZ	moderate	Altered Expression	[4]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Interferon-induced 35 kDa protein (IFI35).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Interferon-induced 35 kDa protein (IFI35).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Interferon-induced 35 kDa protein (IFI35).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Interferon-induced 35 kDa protein (IFI35).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Interferon-induced 35 kDa protein (IFI35).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Interferon-induced 35 kDa protein (IFI35).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Interferon-induced 35 kDa protein (IFI35).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Interferon-induced 35 kDa protein (IFI35).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Interferon-induced 35 kDa protein (IFI35).	[14]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Interferon-induced 35 kDa protein (IFI35).	[14]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Interferon-induced 35 kDa protein (IFI35).	[15]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Interferon-induced 35 kDa protein (IFI35).	[16]
Selenium	DM25CGV	Approved	Selenium increases the expression of Interferon-induced 35 kDa protein (IFI35).	[17]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Interferon-induced 35 kDa protein (IFI35).	[18]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Interferon-induced 35 kDa protein (IFI35).	[19]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Interferon-induced 35 kDa protein (IFI35).	[16]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the expression of Interferon-induced 35 kDa protein (IFI35).	[16]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Interferon-induced 35 kDa protein (IFI35).	[20]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Interferon-induced 35 kDa protein (IFI35).	[21]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of Interferon-induced 35 kDa protein (IFI35).	[16]
Tofacitinib	DMBS370	Approved	Tofacitinib decreases the expression of Interferon-induced 35 kDa protein (IFI35).	[22]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Interferon-induced 35 kDa protein (IFI35).	[23]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Interferon-induced 35 kDa protein (IFI35).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Interferon-induced 35 kDa protein (IFI35).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Interferon-induced 35 kDa protein (IFI35).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Interferon-induced 35 kDa protein (IFI35).	[25]

References

• [1] Interferon (IFN)-induced protein 35 (IFI35) negatively regulates IFN--phosphorylated STAT1-RIG-I-CXCL10/CCL5 axis in U373MG astrocytoma cells treated with polyinosinic-polycytidylic acid.Brain Res. 2017 Mar 1;1658:60-67. doi: 10.1016/j.brainres.2017.01.018. Epub 2017 Jan 19.
• [2] Interferon (IFN)-Induced Protein 35 (IFI35), a Type I Interferon-Dependent Transcript, Upregulates Inflammatory Signaling Pathways by Activating Toll-Like Receptor 3 in Human Mesangial Cells.Kidney Blood Press Res. 2016;41(5):635-642. doi: 10.1159/000447932. Epub 2016 Sep 17.
• [3] A host transcriptional signature for presymptomatic detection of infection in humans exposed to influenza H1N1 or H3N2.PLoS One. 2013;8(1):e52198. doi: 10.1371/journal.pone.0052198. Epub 2013 Jan 9.
• [4] The role of IFI35 in lupus nephritis and related mechanisms.Mod Rheumatol. 2017 Nov;27(6):1010-1018. doi: 10.1080/14397595.2016.1270387. Epub 2017 Jan 13.
• [5] The physiologic increase in expression of some type I IFN-inducible genes during pregnancy is not associated with improved disease activity in pregnant patients with rheumatoid arthritis.Transl Res. 2013 Jun;161(6):505-12. doi: 10.1016/j.trsl.2013.02.007. Epub 2013 Mar 16.
• [6] 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.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [9] 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.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [12] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [13] 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.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [16] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [17] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [18] 5-Fluorouracil up-regulates interferon pathway gene expression in esophageal cancer cells. Anticancer Res. 2005 Sep-Oct;25(5):3271-8.
• [19] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [20] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [21] Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers. J Allergy Clin Immunol. 2016 Dec;138(6):1690-1700. doi: 10.1016/j.jaci.2016.02.038. Epub 2016 Apr 24.
• [22] White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nat Cell Biol. 2015 Jan;17(1):57-67. doi: 10.1038/ncb3075. Epub 2014 Dec 8.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [25] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.