Details of Drug Off-Target (DOT)

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

• DOT Name: Nuclear factor of activated T-cells, cytoplasmic 3 (NFATC3)
• Synonyms: NF-ATc3; NFATc3; NFATx; T-cell transcription factor NFAT4; NF-AT4; NF-AT4c
• Gene Name: NFATC3
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Astrocytoma
  Atrial fibrillation
  Bipolar disorder
  Breast carcinoma
  Chronic obstructive pulmonary disease
  Colorectal carcinoma
  Dementia
  Glioma
  High blood pressure
  leukaemia
  Leukemia
  Neoplasm
  Obesity
  Pneumonia
  Pneumonitis
  Prostate neoplasm
  Pulmonary arterial hypertension
  Squamous cell carcinoma
  T-cell acute lymphoblastic leukaemia
  Bacterial infection
  Type-1/2 diabetes
  Glaucoma/ocular hypertension
  Schizophrenia
• UniProt ID: NFAC3_HUMAN
• PDB ID: 2XRW; 2XS0
• Pfam ID: PF16179 ; PF00554
• Sequence:
  MTTANCGAHDELDFKLVFGEDGAPAPPPPGSRPADLEPDDCASIYIFNVDPPPSTLTTPL
  CLPHHGLPSHSSVLSPSFQLQSHKNYEGTCEIPESKYSPLGGPKPFECPSIQITSISPNC
  HQELDAHEDDLQINDPEREFLERPSRDHLYLPLEPSYRESSLSPSPASSISSRSWFSDAS
  SCESLSHIYDDVDSELNEAAARFTLGSPLTSPGGSPGGCPGEETWHQQYGLGHSLSPRQS
  PCHSPRSSVTDENWLSPRPASGPSSRPTSPCGKRRHSSAEVCYAGSLSPHHSPVPSPGHS
  PRGSVTEDTWLNASVHGGSGLGPAVFPFQYCVETDIPLKTRKTSEDQAAILPGKLELCSD
  DQGSLSPARETSIDDGLGSQYPLKKDSCGDQFLSVPSPFTWSKPKPGHTPIFRTSSLPPL
  DWPLPAHFGQCELKIEVQPKTHHRAHYETEGSRGAVKASTGGHPVVKLLGYNEKPINLQM
  FIGTADDRYLRPHAFYQVHRITGKTVATASQEIIIASTKVLEIPLLPENNMSASIDCAGI
  LKLRNSDIELRKGETDIGRKNTRVRLVFRVHIPQPSGKVLSLQIASIPVECSQRSAQELP
  HIEKYSINSCSVNGGHEMVVTGSNFLPESKIIFLEKGQDGRPQWEVEGKIIREKCQGAHI
  VLEVPPYHNPAVTAAVQVHFYLCNGKRKKSQSQRFTYTPVLMKQEHREEIDLSSVPSLPV
  PHPAQTQRPSSDSGCSHDSVLSGQRSLICSIPQTYASMVTSSHLPQLQCRDESVSKEQHM
  IPSPIVHQPFQVTPTPPVGSSYQPMQTNVVYNGPTCLPINAASSQEFDSVLFQQDATLSG
  LVNLGCQPLSSIPFHSSNSGSTGHLLAHTPHSVHTLPHLQSMGYHCSNTGQRSLSSPVAD
  QITGQPSSQLQPITYGPSHSGSATTASPAASHPLASSPLSGPPSPQLQPMPYQSPSSGTA
  SSPSPATRMHSGQHSTQAQSTGQGGLSAPSSLICHSLCDPASFPPDGATVSIKPEPEDRE
  PNFATIGLQDITLDDVNEIIGRDMSQISVSQGAGVSRQAPLPSPESLDLGRSDGL
• Function: Acts as a regulator of transcriptional activation. Binds to the TNFSF11/RANKL promoter region and promotes TNFSF11 transcription. Binding to the TNFSF11 promoter region is increased by high levels of Ca(2+) which induce NFATC3 expression and may lead to regulation of TNFSF11 expression in osteoblasts. Plays a role in promoting mesenteric arterial wall remodeling in response to the intermittent hypoxia-induced increase in EDN1 and ROCK signaling. As a result NFATC3 colocalizes with F-actin filaments, translocates to the nucleus and promotes transcription of the smooth muscle hypertrophy and differentiation marker ACTA2. Promotes lipopolysaccharide-induced apoptosis and hypertrophy in cardiomyocytes. Following JAK/STAT signaling activation and as part of a complex with NFATC4 and STAT3, binds to the alpha-beta E4 promoter region of CRYAB and activates transcription in cardiomyocytes. In conjunction with NFATC4, involved in embryonic heart development via maintenance of cardiomyocyte survival, proliferation and differentiation. Plays a role in the inducible expression of cytokine genes in T-cells, especially in the induction of the IL-2. Required for thymocyte maturation during DN3 to DN4 transition and during positive selection. Positively regulates macrophage-derived polymicrobial clearance, via binding to the promoter region and promoting transcription of NOS2 resulting in subsequent generation of nitric oxide.
• Tissue Specificity: .Predominantly expressed in thymus and is also found in peripheral blood leukocytes and kidney.; [Isoform 2]: Predominantly expressed in skeletal muscle . Also found weakly expressed in the thymus, kidney, testis, spleen, prostate, ovary, small intestine, heart, placenta and pancreas .; [Isoform 3]: Expressed in thymus and kidney.; [Isoform 4]: Expressed in thymus and skeletal muscle.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  Efferocytosis (hsa04148)
  Cellular senescence (hsa04218)
  Wnt sig.ling pathway (hsa04310)
  Axon guidance (hsa04360)
  C-type lectin receptor sig.ling pathway (hsa04625)
  Th1 and Th2 cell differentiation (hsa04658)
  Th17 cell differentiation (hsa04659)
  T cell receptor sig.ling pathway (hsa04660)
  B cell receptor sig.ling pathway (hsa04662)
  Oxytocin sig.ling pathway (hsa04921)
  Yersinia infection (hsa05135)
  Hepatitis B (hsa05161)
  Human cytomegalovirus infection (hsa05163)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Human immunodeficiency virus 1 infection (hsa05170)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  FCERI mediated Ca+2 mobilization (R-HSA-2871809)
  CLEC7A (Dectin-1) induces NFAT activation (R-HSA-5607763)
  Calcineurin activates NFAT (R-HSA-2025928)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
Astrocytoma	DISL3V18	Strong	Altered Expression	[3]
Atrial fibrillation	DIS15W6U	Strong	Altered Expression	[4]
Bipolar disorder	DISAM7J2	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Dementia	DISXL1WY	Strong	Biomarker	[9]
Glioma	DIS5RPEH	Strong	Biomarker	[10]
High blood pressure	DISY2OHH	Strong	Biomarker	[11]
leukaemia	DISS7D1V	Strong	Biomarker	[12]
Leukemia	DISNAKFL	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Altered Expression	[13]
Obesity	DIS47Y1K	Strong	Biomarker	[14]
Pneumonia	DIS8EF3M	Strong	Biomarker	[15]
Pneumonitis	DIS88E0K	Strong	Biomarker	[15]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[16]
Pulmonary arterial hypertension	DISP8ZX5	Strong	Biomarker	[17]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[1]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Biomarker	[18]
Bacterial infection	DIS5QJ9S	moderate	Altered Expression	[19]
Type-1/2 diabetes	DISIUHAP	moderate	Altered Expression	[20]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Altered Expression	[21]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[22]

4 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 Nuclear factor of activated T-cells, cytoplasmic 3 (NFATC3).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Nuclear factor of activated T-cells, cytoplasmic 3 (NFATC3).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Nuclear factor of activated T-cells, cytoplasmic 3 (NFATC3).	[37]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Nuclear factor of activated T-cells, cytoplasmic 3 (NFATC3).	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin affects the localization of Nuclear factor of activated T-cells, cytoplasmic 3 (NFATC3).	[24]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the localization of Nuclear factor of activated T-cells, cytoplasmic 3 (NFATC3).	[30]
Harmine	DMPA5WD	Patented	Harmine affects the localization of Nuclear factor of activated T-cells, cytoplasmic 3 (NFATC3).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Nuclear factor of activated T-cells, cytoplasmic 3 (NFATC3).	[25]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Nuclear factor of activated T-cells, cytoplasmic 3 (NFATC3).	[26]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Nuclear factor of activated T-cells, cytoplasmic 3 (NFATC3).	[24]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Nuclear factor of activated T-cells, cytoplasmic 3 (NFATC3).	[27]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Nuclear factor of activated T-cells, cytoplasmic 3 (NFATC3).	[28]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Nuclear factor of activated T-cells, cytoplasmic 3 (NFATC3).	[29]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline decreases the expression of Nuclear factor of activated T-cells, cytoplasmic 3 (NFATC3).	[31]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Nuclear factor of activated T-cells, cytoplasmic 3 (NFATC3).	[32]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Nuclear factor of activated T-cells, cytoplasmic 3 (NFATC3).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Nuclear factor of activated T-cells, cytoplasmic 3 (NFATC3).	[34]

References

• [1] NFATc3 plays an oncogenic role in oral/oropharyngeal squamous cell carcinomas by promoting cancer stemness via expression of OCT4.Oncotarget. 2019 Mar 19;10(23):2306-2319. doi: 10.18632/oncotarget.26774. eCollection 2019 Mar 19.
• [2] Ca(2+), Astrocyte Activation and Calcineurin/NFAT Signaling in Age-Related Neurodegenerative Diseases.Front Aging Neurosci. 2018 Jul 9;10:199. doi: 10.3389/fnagi.2018.00199. eCollection 2018.
• [3] NFAT4 is expressed in primary astrocytes and activated by glutamate.J Neurosci Res. 2003 Apr 15;72(2):191-7. doi: 10.1002/jnr.10584.
• [4] Increased expression of NF-AT3 and NF-AT4 in the atria correlates with procollagen I carboxyl terminal peptide and TGF-1 levels in serum of patients with atrial fibrillation.BMC Cardiovasc Disord. 2014 Nov 25;14:167. doi: 10.1186/1471-2261-14-167.
• [5] Exploring the Wnt signaling pathway in schizophrenia and bipolar disorder.Transl Psychiatry. 2018 Mar 6;8(1):55. doi: 10.1038/s41398-018-0102-1.
• [6] The role of calcineurin/NFAT in SFRP2 induced angiogenesis--a rationale for breast cancer treatment with the calcineurin inhibitor tacrolimus.PLoS One. 2011;6(6):e20412. doi: 10.1371/journal.pone.0020412. Epub 2011 Jun 3.
• [7] NFATc3 and VIP in Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease.PLoS One. 2017 Jan 26;12(1):e0170606. doi: 10.1371/journal.pone.0170606. eCollection 2017.
• [8] NFATC3-PLA2G15 Fusion Transcript Identified by RNA Sequencing Promotes Tumor Invasion and Proliferation in Colorectal Cancer Cell Lines.Cancer Res Treat. 2019 Jan;51(1):391-401. doi: 10.4143/crt.2018.103. Epub 2018 Jun 14.
• [9] Calcineurin/NFAT Signaling in Activated Astrocytes Drives Network Hyperexcitability in A-Bearing Mice.J Neurosci. 2017 Jun 21;37(25):6132-6148. doi: 10.1523/JNEUROSCI.0877-17.2017. Epub 2017 May 30.
• [10] NFATc3 controls tumour growth by regulating proliferation and migration of human astroglioma cells.Sci Rep. 2019 Jun 27;9(1):9361. doi: 10.1038/s41598-019-45731-w.
• [11] Regulation of soluble guanylyl cyclase-alpha1 expression in chronic hypoxia-induced pulmonary hypertension: role of NFATc3 and HuR.Am J Physiol Lung Cell Mol Physiol. 2009 Sep;297(3):L475-86. doi: 10.1152/ajplung.00060.2009. Epub 2009 Jul 10.
• [12] Chromosome band 16q22-linked familial AML: exclusion of candidate genes, and possible disease risk modification by NQO1 polymorphisms.Genes Chromosomes Cancer. 2004 Nov;41(3):278-82. doi: 10.1002/gcc.20084.
• [13] Linc00423 as a tumor suppressor in retroperitoneal liposarcoma via activing MAPK signaling pathway through destabilizing of NFATC3.Cell Death Dis. 2019 Jun 3;10(6):430. doi: 10.1038/s41419-019-1658-2.
• [14] NFATc3 deficiency reduces the classical activation of adipose tissue macrophages.J Mol Endocrinol. 2018 Oct 1;61(3):79-89. doi: 10.1530/JME-18-0070.
• [15] Inhibition of nuclear factor of activated T cells (NFAT) c3 activation attenuates acute lung injury and pulmonary edema in murine models of sepsis.Oncotarget. 2018 Jan 25;9(12):10606-10620. doi: 10.18632/oncotarget.24320. eCollection 2018 Feb 13.
• [16] An infectious retrovirus susceptible to an IFN antiviral pathway from human prostate tumors.Proc Natl Acad Sci U S A. 2007 Jan 30;104(5):1655-60. doi: 10.1073/pnas.0610291104. Epub 2007 Jan 18.
• [17] Sarpogrelate attenuates pulmonary arterial hypertension via calcium/calcineurin axis.Front Biosci (Landmark Ed). 2019 Jan 1;24(4):607-615. doi: 10.2741/4739.
• [18] Novel Intergenically Spliced Chimera, NFATC3-PLA2G15, Is Associated with Aggressive T-ALL Biology and Outcome.Mol Cancer Res. 2018 Mar;16(3):470-475. doi: 10.1158/1541-7786.MCR-17-0442. Epub 2018 Jan 12.
• [19] Characterization of nuclear factor of activated T-cells-c3 (NFATc3) and gene expression of upstream-downstream signaling molecules in response to immunostimulants in Pacific red snapper cells.Dev Comp Immunol. 2018 Jan;78:149-159. doi: 10.1016/j.dci.2017.10.001. Epub 2017 Oct 3.
• [20] Nuclear factor of activated T cells regulates osteopontin expression in arterial smooth muscle in response to diabetes-induced hyperglycemia.Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):218-24. doi: 10.1161/ATVBAHA.109.199299. Epub 2009 Dec 3.
• [21] Activation of the NFAT-Calcium Signaling Pathway in Human Lamina Cribrosa Cells in Glaucoma.Invest Ophthalmol Vis Sci. 2018 Feb 1;59(2):831-842. doi: 10.1167/iovs.17-22531.
• [22] Association of Schizophrenia Risk With Disordered Niacin Metabolism in an Indian Genome-wide Association Study.JAMA Psychiatry. 2019 Oct 1;76(10):1026-1034. doi: 10.1001/jamapsychiatry.2019.1335.
• [23] 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.
• [24] Arsenic sulfide induces RAG1-dependent DNA damage for cell killing by inhibiting NFATc3 in gastric cancer cells. J Exp Clin Cancer Res. 2019 Dec 10;38(1):487. doi: 10.1186/s13046-019-1471-x.
• [25] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [26] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [27] A comprehensive analysis of Wnt/beta-catenin signaling pathway-related genes and crosstalk pathways in the treatment of As2O3 in renal cancer. Ren Fail. 2018 Nov;40(1):331-339.
• [28] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [29] Ethanol enhances arsenic-induced cyclooxygenase-2 expression via both NFAT and NF-B signalings in colorectal cancer cells. Toxicol Appl Pharmacol. 2015 Oct 15;288(2):232-9.
• [30] Simvastatin stimulates production of the antiapoptotic protein Bcl-2 via endothelin-1 and NFATc3 in SH-SY5Y cells. Mol Neurobiol. 2010 Jun;41(2-3):384-91. doi: 10.1007/s12035-010-8122-8. Epub 2010 Apr 6.
• [31] 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.
• [32] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [33] 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.
• [34] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [35] 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.
• [36] A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nat Med. 2015 Apr;21(4):383-8. doi: 10.1038/nm.3820. Epub 2015 Mar 9.
• [37] 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.