Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNW949D)

• DOT Name: Protein Tob1 (TOB1)
• Synonyms: Transducer of erbB-2 1
• Gene Name: TOB1
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Chondrosarcoma
  Colon cancer
  Colon carcinoma
  Endometriosis
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Multiple sclerosis
  Neoplasm
  Nervous system inflammation
  Non-small-cell lung cancer
  Obesity
  Stomach cancer
  Gastric cancer
  Neuroblastoma
  Autoimmune disease
• UniProt ID: TOB1_HUMAN
• PDB ID: 2D5R; 2Z15; 5CI8; 5CI9
• Pfam ID: PF07742
• Sequence:
  MQLEIQVALNFIISYLYNKLPRRRVNIFGEELERLLKKKYEGHWYPEKPYKGSGFRCIHI
  GEKVDPVIEQASKESGLDIDDVRGNLPQDLSVWIDPFEVSYQIGEKGPVKVLYVDDNNEN
  GCELDKEIKNSFNPEAQVFMPISDPASSVSSSPSPPFGHSAAVSPTFMPRSTQPLTFTTA
  TFAATKFGSTKMKNSGRSNKVARTSPINLGLNVNDLLKQKAISSSMHSLYGLGLGSQQQP
  QQQQQPAQPPPPPPPPQQQQQQKTSALSPNAKEFIFPNMQGQGSSTNGMFPGDSPLNLSP
  LQYSNAFDVFAAYGGLNEKSFVDGLNFSLNNMQYSNQQFQPVMAN
• Function: Anti-proliferative protein; the function is mediated by association with deadenylase subunits of the CCR4-NOT complex. Mediates CPEB3-accelerated mRNA deadenylation by binding to CPEB3 and recruiting CNOT7 which leads to target mRNA deadenylation and decay.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: R. degradation (hsa03018)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Chondrosarcoma	DIS4I7JB	Strong	Altered Expression	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Endometriosis	DISX1AG8	Strong	Biomarker	[6]
Lung cancer	DISCM4YA	Strong	Altered Expression	[7]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[7]
Lung neoplasm	DISVARNB	Strong	Posttranslational Modification	[8]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Nervous system inflammation	DISB3X5A	Strong	Biomarker	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[12]
Obesity	DIS47Y1K	Strong	Biomarker	[13]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[14]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[14]
Neuroblastoma	DISVZBI4	moderate	Altered Expression	[15]
Autoimmune disease	DISORMTM	Limited	Altered Expression	[11]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Protein Tob1 (TOB1) affects the response to substance of Methotrexate.	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Protein Tob1 (TOB1).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein Tob1 (TOB1).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein Tob1 (TOB1).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protein Tob1 (TOB1).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein Tob1 (TOB1).	[20]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Protein Tob1 (TOB1).	[21]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protein Tob1 (TOB1).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Protein Tob1 (TOB1).	[23]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Protein Tob1 (TOB1).	[24]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Protein Tob1 (TOB1).	[26]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Protein Tob1 (TOB1).	[27]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Protein Tob1 (TOB1).	[28]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Protein Tob1 (TOB1).	[29]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Protein Tob1 (TOB1).	[30]
Vitamin A	DMJ2AH4	Approved	Vitamin A increases the expression of Protein Tob1 (TOB1).	[31]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein Tob1 (TOB1).	[32]
Phenol	DM1QSM3	Phase 2/3	Phenol decreases the expression of Protein Tob1 (TOB1).	[33]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein Tob1 (TOB1).	[35]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Protein Tob1 (TOB1).	[36]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Protein Tob1 (TOB1).	[37]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Protein Tob1 (TOB1).	[38]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Protein Tob1 (TOB1).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Protein Tob1 (TOB1).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein Tob1 (TOB1).	[34]

References

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• [3] Profile of differentially expressed genes after transfer of chromosome 17 into the breast cancer cell line CAL51.Genes Chromosomes Cancer. 2005 Nov;44(3):233-46. doi: 10.1002/gcc.20240.
• [4] Repression of anti-proliferative factor Tob1 in osteoarthritic cartilage.Arthritis Res Ther. 2005;7(2):R274-84. doi: 10.1186/ar1479. Epub 2005 Jan 11.
• [5] High expression of Tob1 indicates poor survival outcome and promotes tumour progression via a Wnt positive feedback loop in colon cancer.Mol Cancer. 2018 Nov 17;17(1):159. doi: 10.1186/s12943-018-0907-9.
• [6] Molecular evidence for differences in endometrium in severe versus mild endometriosis.Reprod Sci. 2011 Mar;18(3):229-51. doi: 10.1177/1933719110386241. Epub 2010 Nov 9.
• [7] Overexpression of high mobility group protein B1 correlates with the proliferation and metastasis of lung adenocarcinoma cells.Mol Med Rep. 2013 May;7(5):1678-82. doi: 10.3892/mmr.2013.1362. Epub 2013 Mar 6.
• [8] Alteration of expression or phosphorylation status of tob, a novel tumor suppressor gene product, is an early event in lung cancer.Cancer Lett. 2003 Dec 8;202(1):71-9. doi: 10.1016/j.canlet.2003.08.019.
• [9] MicroRNA-590 promotes pathogenic Th17cell differentiation through targeting Tob1 and is associated with multiple sclerosis.Biochem Biophys Res Commun. 2017 Nov 18;493(2):901-908. doi: 10.1016/j.bbrc.2017.09.123. Epub 2017 Sep 23.
• [10] MicroRNA-371a-3p promotes progression of gastric cancer by targeting TOB1.Cancer Lett. 2019 Feb 28;443:179-188. doi: 10.1016/j.canlet.2018.11.021. Epub 2018 Dec 4.
• [11] Tob1 plays a critical role in the activation of encephalitogenic T cells in CNS autoimmunity.J Exp Med. 2013 Jul 1;210(7):1301-9. doi: 10.1084/jem.20121611.
• [12] TOB1-AS1 suppresses non-small cell lung cancer cell migration and invasion through a ceRNA network.Exp Ther Med. 2019 Dec;18(6):4249-4258. doi: 10.3892/etm.2019.8103. Epub 2019 Oct 15.
• [13] Genome-Wide Interaction and Pathway Association Studies for Body Mass Index.Front Genet. 2019 May 1;10:404. doi: 10.3389/fgene.2019.00404. eCollection 2019.
• [14] Decreased expression levels of DAL-1 and TOB1 are associated with clinicopathological features and poor prognosis in gastric cancer.Pathol Res Pract. 2019 Jun;215(6):152403. doi: 10.1016/j.prp.2019.03.031. Epub 2019 Apr 2.
• [15] Genes modulated by histone acetylation as new effectors of butyrate activity.FEBS Lett. 2001 Jun 22;499(3):199-204. doi: 10.1016/s0014-5793(01)02539-x.
• [16] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [21] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [22] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [23] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [24] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [25] 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.
• [26] Analysis of gene expression induced by diethylstilbestrol (DES) in human primitive Mullerian duct cells using microarray. Cancer Lett. 2005 Apr 8;220(2):197-210.
• [27] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [28] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [29] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [30] Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem. 2004 Mar;88(5):1211-9. doi: 10.1046/j.1471-4159.2003.02247.x.
• [31] Suppression of mammary carcinoma cell growth by retinoic acid: the cell cycle control gene Btg2 is a direct target for retinoic acid receptor signaling. Cancer Res. 2007 Jan 15;67(2):609-15. doi: 10.1158/0008-5472.CAN-06-0989.
• [32] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [33] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [34] 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.
• [35] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [36] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [37] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [38] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [39] Drug development for ovarian hyper-stimulation and anti-cancer treatment: blocking of gonadotropin signaling for epiregulin and amphiregulin biosynthesis. Biochem Pharmacol. 2004 Sep 15;68(6):989-96. doi: 10.1016/j.bcp.2004.05.027.
• [40] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.