Details of Drug Off-Target (DOT)

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

• DOT Name: TSC22 domain family protein 4 (TSC22D4)
• Synonyms: TSC22-related-inducible leucine zipper protein 2
• Gene Name: TSC22D4
• Related Disease:
  Neoplasm
  Hyperglycemia
  Neoplasm of esophagus
  Type-1/2 diabetes
• UniProt ID: T22D4_HUMAN
• Pfam ID: PF01166
• Sequence:
  MSGGKKKSSFQITSVTTDYEGPGSPGASDPPTPQPPTGPPPRLPNGEPSPDPGGKGTPRN
  GSPPPGAPSSRFRVVKLPHGLGEPYRRGRWTCVDVYERDLEPHSFGGLLEGIRGASGGAG
  GRSLDSRLELASLGLGAPTPPSGLSQGPTSWLRPPPTSPGPQARSFTGGLGQLVVPSKAK
  AEKPPLSASSPQQRPPEPETGESAGTSRAATPLPSLRVEAEAGGSGARTPPLSRRKAVDM
  RLRMELGAPEEMGQVPPLDSRPSSPALYFTHDASLVHKSPDPFGAVAAQKFSLAHSMLAI
  SGHLDSDDDSGSGSLVGIDNKIEQAMDLVKSHLMFAVREEVEVLKEQIRELAERNAALEQ
  ENGLLRALASPEQLAQLPSSGVPRLGPPAPNGPSV
• Function: Binds DNA and acts as a transcriptional repressor. Involved in the regulation of systematic glucose homeostasis and insulin sensitivity, via transcriptional repression of downstream insulin signaling targets such as OBP2A/LCN13. Acts as a negative regulator of lipogenic gene expression in hepatocytes and thereby mediates the control of very low-density lipoprotein release. May play a role in neurite elongation and survival.
• Tissue Specificity: Expressed in the liver.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Hyperglycemia	DIS0BZB5	Limited	Biomarker	[2]
Neoplasm of esophagus	DISOLKAQ	Limited	Biomarker	[3]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[2]

4 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 TSC22 domain family protein 4 (TSC22D4).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of TSC22 domain family protein 4 (TSC22D4).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of TSC22 domain family protein 4 (TSC22D4).	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of TSC22 domain family protein 4 (TSC22D4).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of TSC22 domain family protein 4 (TSC22D4).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of TSC22 domain family protein 4 (TSC22D4).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of TSC22 domain family protein 4 (TSC22D4).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of TSC22 domain family protein 4 (TSC22D4).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of TSC22 domain family protein 4 (TSC22D4).	[11]

References

• [1] The interplay between TGF--stimulated TSC22 domain family proteins regulates cell-cycle dynamics in medulloblastoma cells.J Cell Physiol. 2019 Aug;234(10):18349-18360. doi: 10.1002/jcp.28468. Epub 2019 Mar 25.
• [2] Control of diabetic hyperglycaemia and insulin resistance through TSC22D4.Nat Commun. 2016 Nov 9;7:13267. doi: 10.1038/ncomms13267.
• [3] Promotion of cellular senescence by THG-1/TSC22D4 knockout through activation of JUNB.Biochem Biophys Res Commun. 2020 Feb 19;522(4):897-902. doi: 10.1016/j.bbrc.2019.11.145. Epub 2019 Dec 3.
• [4] 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.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] 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.
• [7] 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.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.