Details of Drug Off-Target (DOT)

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

• DOT Name: C2 calcium-dependent domain-containing protein 4A (C2CD4A)
• Synonyms: Nuclear-localized factor 1; Protein FAM148A
• Gene Name: C2CD4A
• Related Disease:
  Type-1/2 diabetes
  Non-insulin dependent diabetes
• UniProt ID: C2C4A_HUMAN
• Sequence:
  MWCLERLRLGPECLRRSGDWLLPGRARGAKSRTTAACANVLTPDRIPEFCIPPRLMPRLA
  LAALRNSWVEEAGMDEGAGRTDWDPRSQAALSLPHLPRVRTAYGFCALLESPHTRRKESL
  LLGGPPAPRPRAHTYGGGGGPDALLGTLRVPRAPGPATPAAPGCPRPPQDALARRPRGCR
  LLRVPDGLLSRALRAGRSRRLTRVRSVSSGNEDKERRAGSQSPARAPSTSPPSSRVPFPE
  RLEAEGTVALGRAGDALRLAAEYCPGTGRLRLRLLRAESPAGGAPGPRAVSCRLSLVLRP
  PGTALRQCSTVVGRSRKASFDQDFCFDGLSEDEVRRLAVRVKARDEGRGRERGRLLGQGE
  LSLGALLLL
• Function: May be involved in inflammatory process. May regulate cell architecture and adhesion.
• Tissue Specificity: Specifically expressed in endothelial cells.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[1]
Non-insulin dependent diabetes	DISK1O5Z	moderate	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of C2 calcium-dependent domain-containing protein 4A (C2CD4A).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of C2 calcium-dependent domain-containing protein 4A (C2CD4A).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of C2 calcium-dependent domain-containing protein 4A (C2CD4A).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of C2 calcium-dependent domain-containing protein 4A (C2CD4A).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of C2 calcium-dependent domain-containing protein 4A (C2CD4A).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of C2 calcium-dependent domain-containing protein 4A (C2CD4A).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of C2 calcium-dependent domain-containing protein 4A (C2CD4A).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of C2 calcium-dependent domain-containing protein 4A (C2CD4A).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of C2 calcium-dependent domain-containing protein 4A (C2CD4A).	[9]

References

• [1] Identification of C2CD4A as a human diabetes susceptibility gene with a role in cell insulin secretion.Proc Natl Acad Sci U S A. 2019 Oct 1;116(40):20033-20042. doi: 10.1073/pnas.1904311116. Epub 2019 Sep 16.
• [2] A Common Type 2 Diabetes Risk Variant Potentiates Activity of an Evolutionarily Conserved Islet Stretch Enhancer and Increases C2CD4A and C2CD4B Expression.Am J Hum Genet. 2018 Apr 5;102(4):620-635. doi: 10.1016/j.ajhg.2018.02.020.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] 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.
• [5] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [6] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [7] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [8] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [9] 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.
• [10] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [11] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.