Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZZO56M)

• DOT Name: Tubulointerstitial nephritis antigen-like (TINAGL1)
• Synonyms: Glucocorticoid-inducible protein 5; Oxidized LDL-responsive gene 2 protein; OLRG-2; Tubulointerstitial nephritis antigen-related protein; TIN Ag-related protein; TIN-Ag-RP
• Gene Name: TINAGL1
• Related Disease:
  Drug dependence
  Cleft lip/palate
  Colorectal carcinoma
  Craniosynostosis
  Disorder of sexual differentiation
  Hepatocellular carcinoma
  Keloid
  Melanoma
  Myocardial infarction
  Non-small-cell lung cancer
  Rheumatoid arthritis
  Triple negative breast cancer
  Encephalitis
  Plasma cell myeloma
  Parkinson disease
  Adult glioblastoma
  Breast cancer
  Breast carcinoma
  Glioblastoma multiforme
  Stroke
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
• UniProt ID: TINAL_HUMAN
• Pfam ID: PF00112
• Sequence:
  MWRCPLGLLLLLPLAGHLALGAQQGRGRRELAPGLHLRGIRDAGGRYCQEQDLCCRGRAD
  DCALPYLGAICYCDLFCNRTVSDCCPDFWDFCLGVPPPFPPIQGCMHGGRIYPVLGTYWD
  NCNRCTCQENRQWQCDQEPCLVDPDMIKAINQGNYGWQAGNHSAFWGMTLDEGIRYRLGT
  IRPSSSVMNMHEIYTVLNPGEVLPTAFEASEKWPNLIHEPLDQGNCAGSWAFSTAAVASD
  RVSIHSLGHMTPVLSPQNLLSCDTHQQQGCRGGRLDGAWWFLRRRGVVSDHCYPFSGRER
  DEAGPAPPCMMHSRAMGRGKRQATAHCPNSYVNNNDIYQVTPVYRLGSNDKEIMKELMEN
  GPVQALMEVHEDFFLYKGGIYSHTPVSLGRPERYRRHGTHSVKITGWGEETLPDGRTLKY
  WTAANSWGPAWGERGHFRIVRGVNECDIESFVLGVWGRVGMEDMGHH
• Function: May be implicated in the adrenocortical zonation and in mechanisms for repressing the CYP11B1 gene expression in adrenocortical cells. This is a non catalytic peptidase C1 family protein.
• Tissue Specificity: Highly expressed in aorta, heart, placenta, kidney and a colorectal adenocarcinoma cell line. Moderately expressed in skeletal muscle, pancreas, lung, lymph nodes, adrenal gland, bone marrow and thyroid. Weakly expressed in colon, small intestine, ovary, spleen, testis and prostate. Predominantly found in vascular smooth muscle cells, but also in cardiac and skeletal muscle cells as well as kidney.

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Drug dependence	DIS9IXRC	Definitive	Genetic Variation	[1]
Cleft lip/palate	DIS14IG3	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Craniosynostosis	DIS6J405	Strong	Biomarker	[2]
Disorder of sexual differentiation	DISRMAEZ	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Keloid	DISV09JY	Strong	Biomarker	[6]
Melanoma	DIS1RRCY	Strong	Biomarker	[7]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[9]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[10]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[11]
Encephalitis	DISLD1RL	moderate	Altered Expression	[12]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[13]
Parkinson disease	DISQVHKL	Disputed	Altered Expression	[14]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[15]
Breast cancer	DIS7DPX1	Limited	Biomarker	[16]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[16]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[15]
Stroke	DISX6UHX	Limited	Altered Expression	[17]
Thyroid cancer	DIS3VLDH	Limited	Altered Expression	[18]
Thyroid gland carcinoma	DISMNGZ0	Limited	Altered Expression	[18]
Thyroid tumor	DISLVKMD	Limited	Altered Expression	[18]

3 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 Tubulointerstitial nephritis antigen-like (TINAGL1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Tubulointerstitial nephritis antigen-like (TINAGL1).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Tubulointerstitial nephritis antigen-like (TINAGL1).	[28]

7 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 Tubulointerstitial nephritis antigen-like (TINAGL1).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tubulointerstitial nephritis antigen-like (TINAGL1).	[21]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Tubulointerstitial nephritis antigen-like (TINAGL1).	[22]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Tubulointerstitial nephritis antigen-like (TINAGL1).	[23]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Tubulointerstitial nephritis antigen-like (TINAGL1).	[24]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Tubulointerstitial nephritis antigen-like (TINAGL1).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Tubulointerstitial nephritis antigen-like (TINAGL1).	[27]

References

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• [5] TINAGL1 promotes hepatocellular carcinogenesis through the activation of TGF- signaling-medicated VEGF expression.Cancer Manag Res. 2019 Jan 15;11:767-775. doi: 10.2147/CMAR.S190390. eCollection 2019.
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• [7] Replacing Mn(2+) with Co(2+) in human arginase i enhances cytotoxicity toward l-arginine auxotrophic cancer cell lines.ACS Chem Biol. 2010 Mar 19;5(3):333-42. doi: 10.1021/cb900267j.
• [8] Association of rs2781666 G/T polymorphism of arginase I gene with myocardial infarction in Tunisian male population.Clin Biochem. 2010 Jan;43(1-2):106-9. doi: 10.1016/j.clinbiochem.2009.10.058. Epub 2009 Nov 5.
• [9] Puerarin inhibits M2 polarization and metastasis of tumor-associated macrophages from NSCLC xenograft model via inactivating MEK/ERK 1/2 pathway.Int J Oncol. 2017 Feb;50(2):545-554. doi: 10.3892/ijo.2017.3841. Epub 2017 Jan 5.
• [10] Increased circulating myeloid-derived suppressor cells correlated negatively with Th17 cells in patients with rheumatoid arthritis.Scand J Rheumatol. 2013;42(2):85-90. doi: 10.3109/03009742.2012.716450. Epub 2012 Nov 6.
• [11] Tinagl1 Suppresses Triple-Negative Breast Cancer Progression and Metastasis by Simultaneously Inhibiting Integrin/FAK and EGFR Signaling.Cancer Cell. 2019 Jan 14;35(1):64-80.e7. doi: 10.1016/j.ccell.2018.11.016. Epub 2019 Jan 3.
• [12] The inhibitory role of intracellular free zinc in the regulation of Arg-1 expression in interleukin-4-induced activation of M2 microglia.Metallomics. 2018 Oct 17;10(10):1501-1509. doi: 10.1039/c8mt00248g. Epub 2018 Sep 12.
• [13] PMN-MDSC and arginase are increased in myeloma and may contribute to resistance to therapy.Expert Rev Mol Diagn. 2018 Jul;18(7):675-683. doi: 10.1080/14737159.2018.1470929. Epub 2018 May 3.
• [14] Mild Inflammatory Profile without Gliosis in the c-Rel Deficient Mouse Modeling a Late-Onset Parkinsonism.Front Aging Neurosci. 2017 Jul 19;9:229. doi: 10.3389/fnagi.2017.00229. eCollection 2017.
• [15] Expression of iNOS, CD163 and ARG-1 taken as M1 and M2 markers of microglial polarization in human glioblastoma and the surrounding normal parenchyma.Neurosci Lett. 2017 Apr 3;645:106-112. doi: 10.1016/j.neulet.2017.02.076. Epub 2017 Mar 2.
• [16] Improvement of implantation potential in mouse blastocysts derived from IVF by combined treatment with prolactin, epidermal growth factor and 4-hydroxyestradiol.Mol Hum Reprod. 2017 Aug 1;23(8):557-570. doi: 10.1093/molehr/gax035.
• [17] Rosiglitazone ameliorates tissue plasminogen activator-induced brain hemorrhage after stroke.CNS Neurosci Ther. 2019 Dec;25(12):1343-1352. doi: 10.1111/cns.13260. Epub 2019 Nov 22.
• [18] Long non-coding RNA NEAT1 promotes malignant progression of thyroid carcinoma by regulating miRNA-214.Int J Oncol. 2017 Feb;50(2):708-716. doi: 10.3892/ijo.2016.3803. Epub 2016 Dec 14.
• [19] 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.
• [20] Constitutive gene expression predisposes morphogen-mediated cell fate responses of NT2/D1 and 27X-1 human embryonal carcinoma cells. Stem Cells. 2007 Mar;25(3):771-8. doi: 10.1634/stemcells.2006-0271. Epub 2006 Nov 30.
• [21] 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.
• [22] 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.
• [23] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [24] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [25] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [26] 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.
• [27] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [28] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.