Details of Drug Off-Target (DOT)

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

• DOT Name: Nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4)
• Synonyms: NF-ATc4; NFATc4; T-cell transcription factor NFAT3; NF-AT3
• Gene Name: NFATC4
• Related Disease:
  Glioma
  Alzheimer disease
  Atrial fibrillation
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cardiac failure
  Congestive heart failure
  Huntington disease
  Neoplasm
  Osteoarthritis
  Psoriasis
  Singleton-Merten dysplasia
  Singleton-Merten syndrome 2
  Skin cancer
  Adenovirus infection
  Retinopathy
  Sensorineural hearing loss disorder
  Type-1/2 diabetes
  Asthma
  Noonan syndrome with multiple lentigines
  Post-traumatic stress disorder
• UniProt ID: NFAC4_HUMAN
• PDB ID: 2YRP
• Pfam ID: PF16179 ; PF00554
• Sequence:
  MGAASCEDEELEFKLVFGEEKEAPPLGAGGLGEELDSEDAPPCCRLALGEPPPYGAAPIG
  IPRPPPPRPGMHSPPPRPAPSPGTWESQPARSVRLGGPGGGAGGAGGGRVLECPSIRITS
  ISPTPEPPAALEDNPDAWGDGSPRDYPPPEGFGGYREAGGQGGGAFFSPSPGSSSLSSWS
  FFSDASDEAALYAACDEVESELNEAASRFGLGSPLPSPRASPRPWTPEDPWSLYGPSPGG
  RGPEDSWLLLSAPGPTPASPRPASPCGKRRYSSSGTPSSASPALSRRGSLGEEGSEPPPP
  PPLPLARDPGSPGPFDYVGAPPAESIPQKTRRTSSEQAVALPRSEEPASCNGKLPLGAEE
  SVAPPGGSRKEVAGMDYLAVPSPLAWSKARIGGHSPIFRTSALPPLDWPLPSQYEQLELR
  IEVQPRAHHRAHYETEGSRGAVKAAPGGHPVVKLLGYSEKPLTLQMFIGTADERNLRPHA
  FYQVHRITGKMVATASYEAVVSGTKVLEMTLLPENNMAANIDCAGILKLRNSDIELRKGE
  TDIGRKNTRVRLVFRVHVPQGGGKVVSVQAASVPIECSQRSAQELPQVEAYSPSACSVRG
  GEELVLTGSNFLPDSKVVFIERGPDGKLQWEEEATVNRLQSNEVTLTLTVPEYSNKRVSR
  PVQVYFYVSNGRRKRSPTQSFRFLPVICKEEPLPDSSLRGFPSASATPFGTDMDFSPPRP
  PYPSYPHEDPACETPYLSEGFGYGMPPLYPQTGPPPSYRPGLRMFPETRGTTGCAQPPAV
  SFLPRPFPSDPYGGRGSSFSLGLPFSPPAPFRPPPLPASPPLEGPFPSQSDVHPLPAEGY
  NKVGPGYGPGEGAPEQEKSRGGYSSGFRDSVPIQGITLEEVSEIIGRDLSGFPAPPGEEP
  PA
• Function: Ca(2+)-regulated transcription factor that is involved in several processes, including the development and function of the immune, cardiovascular, musculoskeletal, and nervous systems. Involved in T-cell activation, stimulating the transcription of cytokine genes, including that of IL2 and IL4. Along with NFATC3, involved in embryonic heart development. Following JAK/STAT signaling activation and as part of a complex with NFATC3 and STAT3, binds to the alpha-beta E4 promoter region of CRYAB and activates transcription in cardiomyocytes. Involved in mitochondrial energy metabolism required for cardiac morphogenesis and function. Transactivates many genes involved in the cardiovascular system, including AGTR2, NPPB/BNP (in synergy with GATA4), NPPA/ANP/ANF and MYH7/beta-MHC. Involved in the regulation of adult hippocampal neurogenesis. Involved in BDNF-driven pro-survival signaling in hippocampal adult-born neurons. Involved in the formation of long-term spatial memory and long-term potentiation. In cochlear nucleus neurons, may play a role in deafferentation-induced apoptosis during the developmental critical period, when auditory neurons depend on afferent input for survival. Binds to and activates the BACE1/Beta-secretase 1 promoter, hence may regulate the proteolytic processing of the amyloid precursor protein (APP). Plays a role in adipocyte differentiation. May be involved in myoblast differentiation into myotubes. Binds the consensus DNA sequence 5'-GGAAAAT-3' (Probable). In the presence of CREBBP, activates TNF transcription. Binds to PPARG gene promoter and regulates its activity. Binds to PPARG and REG3G gene promoters.
• Tissue Specificity: Widely expressed, with high levels in placenta, lung, kidney, testis and ovary . Weakly expressed in spleen and thymus . In the hippocampus, expressed in the granular layer of the dentate gyrus, in the pyramidal neurons of CA3 region, and in the hippocampal fissure . Expressed in the heart (at protein level) .
• KEGG Pathway:
  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)
  Oxytocin sig.ling pathway (hsa04921)
  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)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioma	DIS5RPEH	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Atrial fibrillation	DIS15W6U	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Cardiac failure	DISDC067	Strong	Altered Expression	[6]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[6]
Huntington disease	DISQPLA4	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Osteoarthritis	DIS05URM	Strong	Biomarker	[9]
Psoriasis	DIS59VMN	Strong	Altered Expression	[10]
Singleton-Merten dysplasia	DISYNAVB	Strong	Genetic Variation	[11]
Singleton-Merten syndrome 2	DISBYX0D	Strong	Genetic Variation	[11]
Skin cancer	DISTM18U	Strong	Altered Expression	[8]
Adenovirus infection	DISUYSBZ	moderate	Altered Expression	[12]
Retinopathy	DISB4B0F	moderate	Biomarker	[13]
Sensorineural hearing loss disorder	DISJV45Z	moderate	Biomarker	[14]
Type-1/2 diabetes	DISIUHAP	moderate	Genetic Variation	[15]
Asthma	DISW9QNS	Limited	Biomarker	[16]
Noonan syndrome with multiple lentigines	DIS014D0	Limited	Biomarker	[17]
Post-traumatic stress disorder	DISHL1EY	Limited	Biomarker	[18]

1 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 Nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4).	[20]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4).	[21]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4).	[22]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4).	[26]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4).	[29]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Vinblastine	DM5TVS3	Approved	Vinblastine decreases the localization of Nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4).	[24]
Colchicine	DM2POTE	Approved	Colchicine decreases the localization of Nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4).	[24]
Phenylephrine	DMZHUO5	Approved	Phenylephrine increases the localization of Nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4).	[25]
Harmine	DMPA5WD	Patented	Harmine affects the localization of Nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4).	[28]
20-HETE	DM5BAJ9	Investigative	20-HETE increases the localization of Nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4).	[25]

References

• [1] Doxorubicin-mediated apoptosis in glioma cells requires NFAT3.Cell Mol Life Sci. 2009 Dec;66(24):3967-78. doi: 10.1007/s00018-009-0157-5. Epub 2009 Sep 27.
• [2] Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation.J Neurosci. 2010 Feb 17;30(7):2636-49. doi: 10.1523/JNEUROSCI.4456-09.2010.
• [3] 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.
• [4] NFAT3 transcription factor inhibits breast cancer cell motility by targeting the Lipocalin 2 gene.Oncogene. 2010 Apr 15;29(15):2292-301. doi: 10.1038/onc.2009.499. Epub 2010 Jan 25.
• [5] Stimulatory cross-talk between NFAT3 and estrogen receptor in breast cancer cells.J Biol Chem. 2005 Dec 30;280(52):43188-97. doi: 10.1074/jbc.M506598200. Epub 2005 Oct 11.
• [6] Increased regulatory activity of the calcineurin/NFAT pathway in human heart failure.Eur J Heart Fail. 2004 Jan;6(1):3-9. doi: 10.1016/j.ejheart.2003.07.007.
• [7] Lercanidipine boosts the efficacy of mesenchymal stem cell therapy in 3-NP-induced Huntington's disease model rats via modulation of the calcium/calcineurin/NFATc4 and Wnt/-catenin signalling pathways.Neurochem Int. 2019 Dec;131:104548. doi: 10.1016/j.neuint.2019.104548. Epub 2019 Sep 17.
• [8] Phosphorylation of NFAT3 by CDK3 induces cell transformation and promotes tumor growth in skin cancer.Oncogene. 2017 May 18;36(20):2835-2845. doi: 10.1038/onc.2016.434. Epub 2016 Nov 28.
• [9] NFAT3 and TGF-/SMAD3 regulate the expression of miR-140 in osteoarthritis.Arthritis Res Ther. 2013;15(6):R197. doi: 10.1186/ar4387.
• [10] A preliminary examination of the role of NFAT 3 in human skin, cultured keratocytes and dermal fibroblasts.J Cutan Pathol. 2010 Sep;37(9):e21-36. doi: 10.1111/j.1600-0560.2009.01313.x.
• [11] A GTPase-activating protein-binding protein (G3BP1)/antiviral protein relay conveys arteriosclerotic Wnt signals in aortic smooth muscle cells.J Biol Chem. 2018 May 25;293(21):7942-7968. doi: 10.1074/jbc.RA118.002046. Epub 2018 Apr 6.
• [12] SIRT6 Suppresses NFATc4 Expression and Activation in Cardiomyocyte Hypertrophy.Front Pharmacol. 2019 Jan 8;9:1519. doi: 10.3389/fphar.2018.01519. eCollection 2018.
• [13] NFAT isoforms play distinct roles in TNF-induced retinal leukostasis.Sci Rep. 2015 Nov 3;5:14963. doi: 10.1038/srep14963.
• [14] Nfatc4 Deficiency Attenuates Ototoxicity by Suppressing Tnf-Mediated Hair Cell Apoptosis in the Mouse Cochlea.Front Immunol. 2019 Jul 17;10:1660. doi: 10.3389/fimmu.2019.01660. eCollection 2019.
• [15] Genetic polymorphisms of the transcription factor NFATc4 and development of new-onset diabetes after transplantation in Hispanic kidney transplant recipients.Transplantation. 2012 Feb 15;93(3):325-30. doi: 10.1097/TP.0b013e31823f7f26.
• [16] Interleukin-13-induced MUC5AC expression is regulated by a PI3K-NFAT3 pathway in mouse tracheal epithelial cells.Biochem Biophys Res Commun. 2014 Mar 28;446(1):49-53. doi: 10.1016/j.bbrc.2014.02.051. Epub 2014 Feb 26.
• [17] Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome.Nature. 2010 Jun 10;465(7299):808-12. doi: 10.1038/nature09005.
• [18] Involvement of calcineurin/NFATc4 pathway in a single-prolonged stress-based rat model of post-traumatic stress disorder.Mol Biol Rep. 2019 Dec;46(6):6197-6204. doi: 10.1007/s11033-019-05055-4. Epub 2019 Sep 4.
• [19] 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.
• [20] Estrogen Regulates MAPK-Related Genes through Genomic and Nongenomic Interactions between IGF-I Receptor Tyrosine Kinase and Estrogen Receptor-Alpha Signaling Pathways in Human Uterine Leiomyoma Cells. J Signal Transduct. 2012;2012:204236. doi: 10.1155/2012/204236. Epub 2012 Oct 9.
• [21] 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.
• [22] 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.
• [23] NFATc4 mediates ethanol-triggered hepatocyte senescence. Toxicol Lett. 2021 Oct 10;350:10-21. doi: 10.1016/j.toxlet.2021.06.018. Epub 2021 Jun 27.
• [24] Zinc and the cytoskeleton in the neuronal modulation of transcription factor NFAT. J Cell Physiol. 2007 Jan;210(1):246-56. doi: 10.1002/jcp.20861.
• [25] Constrictor-induced translocation of NFAT3 in human and rat pulmonary artery smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2005 Dec;289(6):L1061-74. doi: 10.1152/ajplung.00096.2005. Epub 2005 Jul 29.
• [26] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [27] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [28] 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.
• [29] 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.
• [30] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.