Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT37EWR0)

• DOT Name: BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 2 (TNFAIP1)
• Synonyms: hBACURD2; BTB/POZ domain-containing protein TNFAIP1; Protein B12; Tumor necrosis factor, alpha-induced protein 1, endothelial
• Gene Name: TNFAIP1
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Hepatitis B virus infection
  Imerslund-Grasbeck syndrome
  Neoplasm
  Nervous system disease
  Neuralgia
  Neuroblastoma
  Non-small-cell lung cancer
  Osteosarcoma
  Pancreatic cancer
  Diabetic kidney disease
  Metastatic malignant neoplasm
• UniProt ID: BACD2_HUMAN
• Pfam ID: PF02214
• Sequence:
  MSGDTCLCPASGAKPKLSGFKGGGLGNKYVQLNVGGSLYYTTVRALTRHDTMLKAMFSGR
  MEVLTDKEGWILIDRCGKHFGTILNYLRDDTITLPQNRQEIKELMAEAKYYLIQGLVNMC
  QSALQDKKDSYQPVCNIPIITSLKEEERLIESSTKPVVKLLYNRSNNKYSYTSNSDDHLL
  KNIELFDKLSLRFNGRVLFIKDVIGDEICCWSFYGQGRKLAEVCCTSIVYATEKKQTKVE
  FPEARIYEETLNVLLYETPRVPDNSLLEATSRSRSQASPSEDEETFELRDRVRRIHVKRY
  STYDDRQLGHQSTHRD
• Function: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex involved in regulation of cytoskeleton structure. The BCR(TNFAIP1) E3 ubiquitin ligase complex mediates the ubiquitination of RHOA, leading to its degradation by the proteasome, thereby regulating the actin cytoskeleton and cell migration. Its interaction with RHOB may regulate apoptosis. May enhance the PCNA-dependent DNA polymerase delta activity.
• Reactome Pathway:
  RND2 GTPase cycle (R-HSA-9696270)
  RND3 GTPase cycle (R-HSA-9696264)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[5]
Imerslund-Grasbeck syndrome	DISQ84S1	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[2]
Neuralgia	DISWO58J	Strong	Biomarker	[8]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[9]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[3]
Pancreatic cancer	DISJC981	Strong	Biomarker	[10]
Diabetic kidney disease	DISJMWEY	Limited	Biomarker	[11]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 2 (TNFAIP1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 2 (TNFAIP1).	[16]

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 BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 2 (TNFAIP1).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 2 (TNFAIP1).	[14]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 2 (TNFAIP1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 2 (TNFAIP1).	[17]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 2 (TNFAIP1).	[18]

References

• [1] Knockdown of TNFAIP1 inhibits growth and induces apoptosis in osteosarcoma cells through inhibition of the nuclear factor-B pathway.Oncol Rep. 2014 Sep;32(3):1149-55. doi: 10.3892/or.2014.3291. Epub 2014 Jun 25.
• [2] Knockdown of TNFAIP1 prevents di-(2-ethylhexyl) phthalate-induced neurotoxicity by activating CREB pathway.Chemosphere. 2020 Feb;241:125114. doi: 10.1016/j.chemosphere.2019.125114. Epub 2019 Oct 14.
• [3] MiRNA-15a inhibits proliferation, migration and invasion by targeting TNFAIP1 in human osteosarcoma cells.Int J Clin Exp Pathol. 2015 Jun 1;8(6):6442-9. eCollection 2015.
• [4] Complex sense-antisense architecture of TNFAIP1/POLDIP2 on 17q11.2 represents a novel transcriptional structural-functional gene module involved in breast cancer progression.BMC Genomics. 2010 Feb 10;11 Suppl 1(Suppl 1):S9. doi: 10.1186/1471-2164-11-S1-S9.
• [5] Tumor necrosis factor-alpha-induced protein 1 and immunity to hepatitis B virus.World J Gastroenterol. 2005 Dec 28;11(48):7564-8. doi: 10.3748/wjg.v11.i48.7564.
• [6] Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor-vitamin B(12) by cubilin. Blood. 2000 Jul 15;96(2):405-9.
• [7] MiR-424 Promotes Non-Small Cell Lung Cancer Progression and Metastasis through Regulating the Tumor Suppressor Gene TNFAIP1.Cell Physiol Biochem. 2017;42(1):211-221. doi: 10.1159/000477314. Epub 2017 May 25.
• [8] Effects of XIST/miR-137 axis on neuropathic pain by targeting TNFAIP1 in a rat model.J Cell Physiol. 2018 May;233(5):4307-4316. doi: 10.1002/jcp.26254. Epub 2017 Dec 26.
• [9] MicroRNA-224 is implicated in lung cancer pathogenesis through targeting caspase-3 and caspase-7.Oncotarget. 2015 Sep 8;6(26):21802-15. doi: 10.18632/oncotarget.5224.
• [10] Interaction between microRNA-181a and TNFAIP1 regulates pancreatic cancer proliferation and migration.Tumour Biol. 2015 Dec;36(12):9693-701. doi: 10.1007/s13277-015-3704-8. Epub 2015 Jul 8.
• [11] Hepatic expression profiling shows involvement of PKC epsilon, DGK eta, Tnfaip, and Rho kinase in type 2 diabetic nephropathy rats.J Cell Biochem. 2010 Nov 1;111(4):944-54. doi: 10.1002/jcb.22783.
• [12] 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.
• [13] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [14] 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.
• [15] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [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] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [18] Molecular signatures of cytotoxic effects in human embryonic kidney 293?cells treated with single and mixture of ochratoxin A and citrinin. Food Chem Toxicol. 2019 Jan;123:374-384. doi: 10.1016/j.fct.2018.11.015. Epub 2018 Nov 11.