Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA8OASA)

• DOT Name: Activating signal cointegrator 1 (TRIP4)
• Synonyms: ASC-1; Thyroid receptor-interacting protein 4; TR-interacting protein 4; TRIP-4
• Gene Name: TRIP4
• Related Disease:
  Alzheimer disease
  Cardiomyopathy
  Melanoma
  Myopathy
  Breast carcinoma
  Cervical cancer
  Cervical carcinoma
  Congenital myopathy
  Neoplasm
  Neuromuscular disease
  Prenatal-onset spinal muscular atrophy with congenital bone fractures
  Prostate carcinoma
  Schizophrenia
  Spinal muscular atrophy
  Spinal muscular atrophy with congenital bone fractures 1
  Breast cancer
  Nervous system inflammation
• UniProt ID: TRIP4_HUMAN
• PDB ID: 2E5O; 8ALZ
• Pfam ID: PF04266 ; PF06221
• Sequence:
  MAVAGAVSGEPLVHWCTQQLRKTFGLDVSEEIIQYVLSIESAEEIREYVTDLLQGNEGKK
  GQFIEELITKWQKNDQELISDPLQQCFKKDEILDGQKSGDHLKRGRKKGRNRQEVPAFTE
  PDTTAEVKTPFDLAKAQENSNSVKKKTKFVNLYTREGQDRLAVLLPGRHPCDCLGQKHKL
  INNCLICGRIVCEQEGSGPCLFCGTLVCTHEEQDILQRDSNKSQKLLKKLMSGVENSGKV
  DISTKDLLPHQELRIKSGLEKAIKHKDKLLEFDRTSIRRTQVIDDESDYFASDSNQWLSK
  LERETLQKREEELRELRHASRLSKKVTIDFAGRKILEEENSLAEYHSRLDETIQAIANGT
  LNQPLTKLDRSSEEPLGVLVNPNMYQSPPQWVDHTGAASQKKAFRSSGFGLEFNSFQHQL
  RIQDQEFQEGFDGGWCLSVHQPWASLLVRGIKRVEGRSWYTPHRGRLWIAATAKKPSPQE
  VSELQATYRLLRGKDVEFPNDYPSGCLLGCVDLIDCLSQKQFKEQFPDISQESDSPFVFI
  CKNPQEMVVKFPIKGNPKIWKLDSKIHQGAKKGLMKQNKAV
• Function: Transcription coactivator which associates with nuclear receptors, transcriptional coactivators including EP300, CREBBP and NCOA1, and basal transcription factors like TBP and TFIIA to facilitate nuclear receptors-mediated transcription. May thereby play an important role in establishing distinct coactivator complexes under different cellular conditions. Plays a role in thyroid hormone receptor and estrogen receptor transactivation. Also involved in androgen receptor transactivation. Plays a pivotal role in the transactivation of NF-kappa-B, SRF and AP1. Acts as a mediator of transrepression between nuclear receptor and either AP1 or NF-kappa-B. May play a role in the development of neuromuscular junction. May play a role in late myogenic differentiation. Also functions as part of the RQC trigger (RQT) complex that activates the ribosome quality control (RQC) pathway, a pathway that degrades nascent peptide chains during problematic translation.

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Definitive	Biomarker	[1]
Cardiomyopathy	DISUPZRG	Definitive	Genetic Variation	[2]
Melanoma	DIS1RRCY	Definitive	Biomarker	[3]
Myopathy	DISOWG27	Definitive	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[5]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[5]
Congenital myopathy	DISLSK9G	Strong	Genetic Variation	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Neuromuscular disease	DISQTIJZ	Strong	Genetic Variation	[6]
Prenatal-onset spinal muscular atrophy with congenital bone fractures	DIS9A4XL	Strong	Autosomal recessive	[7]
Prostate carcinoma	DISMJPLE	Strong	Posttranslational Modification	[8]
Schizophrenia	DISSRV2N	Strong	Biomarker	[9]
Spinal muscular atrophy	DISTLKOB	Strong	Biomarker	[2]
Spinal muscular atrophy with congenital bone fractures 1	DISBVYYI	Strong	Autosomal recessive	[7]
Breast cancer	DIS7DPX1	Limited	Biomarker	[4]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Activating signal cointegrator 1 (TRIP4).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Activating signal cointegrator 1 (TRIP4).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Activating signal cointegrator 1 (TRIP4).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Activating signal cointegrator 1 (TRIP4).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Activating signal cointegrator 1 (TRIP4).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Activating signal cointegrator 1 (TRIP4).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Activating signal cointegrator 1 (TRIP4).	[16]

References

• [1] Genetics of Alzheimer's disease.Adv Genet. 2014;87:245-94. doi: 10.1016/B978-0-12-800149-3.00005-6.
• [2] ASC-1 Is a Cell Cycle Regulator Associated with Severe and Mild Forms of Myopathy.Ann Neurol. 2020 Feb;87(2):217-232. doi: 10.1002/ana.25660. Epub 2019 Dec 27.
• [3] The Tumor-Promoting Role of TRIP4 in Melanoma Progression and its Involvement in Response to BRAF-Targeted Therapy.J Invest Dermatol. 2018 Jan;138(1):159-170. doi: 10.1016/j.jid.2017.07.850. Epub 2017 Sep 9.
• [4] Modification of ASC1 by UFM1 is crucial for ER transactivation and breast cancer development.Mol Cell. 2014 Oct 23;56(2):261-274. doi: 10.1016/j.molcel.2014.08.007. Epub 2014 Sep 11.
• [5] TRIP4 promotes tumor growth and metastasis and regulates radiosensitivity of cervical cancer by activating MAPK, PI3K/AKT, and hTERT signaling.Cancer Lett. 2019 Jun 28;452:1-13. doi: 10.1016/j.canlet.2019.03.017. Epub 2019 Mar 21.
• [6] The new neuromuscular disease related with defects in the ASC-1 complex: report of a second case confirms ASCC1 involvement.Clin Genet. 2017 Oct;92(4):434-439. doi: 10.1111/cge.12997. Epub 2017 Mar 31.
• [7] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [8] Coordinate hypermethylation at specific genes in prostate carcinoma precedes LINE-1 hypomethylation.Br J Cancer. 2004 Aug 31;91(5):985-94. doi: 10.1038/sj.bjc.6602030.
• [9] Expression of D-serine and glycine transporters in the prefrontal cortex and cerebellum in schizophrenia.Schizophr Res. 2008 Jul;102(1-3):283-94. doi: 10.1016/j.schres.2008.02.009. Epub 2008 Apr 8.
• [10] Fetuin-A deficiency protects mice from Experimental Autoimmune Encephalomyelitis (EAE) and correlates with altered innate immune response.PLoS One. 2017 Apr 7;12(4):e0175575. doi: 10.1371/journal.pone.0175575. eCollection 2017.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] 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.
• [13] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [14] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [15] 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.
• [16] 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.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.