Details of Drug Off-Target (DOT)

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

• DOT Name: Suppressor of cytokine signaling 4 (SOCS4)
• Synonyms: SOCS-4; Suppressor of cytokine signaling 7; SOCS-7
• Gene Name: SOCS4
• Related Disease:
  Allergic rhinitis
  Alzheimer disease
  Endometrial carcinoma
  Gastric cancer
  Neoplasm
  Precancerous condition
  Stomach cancer
  Autoimmune disease
• UniProt ID: SOCS4_HUMAN
• PDB ID: 2IZV
• Pfam ID: PF00017 ; PF12610 ; PF07525
• Sequence:
  MAENNENISKNVDVRPKTSRSRSADRKDGYVWSGKKLSWSKKSESYSDAETVNGIEKTEV
  SLRNQERKHSCSSIELDLDHSCGHRFLGRSLKQKLQDAVGQCFPIKNCSSRHSSGLPSKR
  KIHISELMLDKCPFPPRSDLAFRWHFIKRHTAPINSKSDEWVSTDLSQTELRDGQLKRRN
  MEENINCFSHTNVQPCVITTDNALCREGPMTGSVMNLVSNNSIEDSDMDSDDEILTLCTS
  SRKRNKPKWDLDDEILQLETPPKYHTQIDYVHCLVPDLLQINNNPCYWGVMDKYAAEALL
  EGKPEGTFLLRDSAQEDYLFSVSFRRYSRSLHARIEQWNHNFSFDAHDPCVFHSPDITGL
  LEHYKDPSACMFFEPLLSTPLIRTFPFSLQHICRTVICNCTTYDGIDALPIPSSMKLYLK
  EYHYKSKVRVLRIDAPEQQC
• Function: SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. Substrate-recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Inhibits EGF signaling by mediating the degradation of the Tyr-phosphorylated EGF receptor/EGFR.
• KEGG Pathway:
  JAK-STAT sig.ling pathway (hsa04630)
  Insulin sig.ling pathway (hsa04910)
  Prolactin sig.ling pathway (hsa04917)
  Type II diabetes mellitus (hsa04930)
• Reactome Pathway: RUNX1 regulates transcription of genes involved in differentiation of keratinocytes (R-HSA-8939242)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Allergic rhinitis	DIS3U9HN	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[3]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Precancerous condition	DISV06FL	Strong	Biomarker	[5]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[4]
Autoimmune disease	DISORMTM	Limited	Autosomal dominant	[6]

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 Suppressor of cytokine signaling 4 (SOCS4).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Suppressor of cytokine signaling 4 (SOCS4).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Suppressor of cytokine signaling 4 (SOCS4).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Suppressor of cytokine signaling 4 (SOCS4).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Suppressor of cytokine signaling 4 (SOCS4).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Suppressor of cytokine signaling 4 (SOCS4).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Suppressor of cytokine signaling 4 (SOCS4).	[13]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Suppressor of cytokine signaling 4 (SOCS4).	[14]

References

• [1] MicroRNA-let-7e regulates the progression and development of allergic rhinitis by targeting suppressor of cytokine signaling 4 and activating Janus kinase 1/signal transducer and activator of transcription 3 pathway.Exp Ther Med. 2018 Apr;15(4):3523-3529. doi: 10.3892/etm.2018.5827. Epub 2018 Feb 1.
• [2] Expression of suppressor of cytokine signaling genes in human elderly and Alzheimer's disease brains and human microglia.Neuroscience. 2015 Aug 27;302:121-37. doi: 10.1016/j.neuroscience.2014.09.052. Epub 2014 Oct 5.
• [3] Long noncoding RNA TUSC7 inhibits cell proliferation, migration and invasion by regulating SOCS4 (SOCS5) expression through targeting miR-616 in endometrial carcinoma.Life Sci. 2019 Aug 15;231:116549. doi: 10.1016/j.lfs.2019.116549. Epub 2019 Jun 12.
• [4] Suppressor of cytokine signaling 4 detected as a novel gastric cancer suppressor gene using double combination array analysis.World J Surg. 2012 Feb;36(2):362-72. doi: 10.1007/s00268-011-1358-2.
• [5] Predominant Activation of JAK/STAT3 Pathway by Interleukin-6 Is Implicated in Hepatocarcinogenesis.Neoplasia. 2015 Jul;17(7):586-97. doi: 10.1016/j.neo.2015.07.005.
• [6] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [9] 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.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] 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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.