Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2N5TCK)

• DOT Name: Integrator complex subunit 2 (INTS2)
• Synonyms: Int2
• Gene Name: INTS2
• Related Disease:
  Advanced cancer
  Carcinoma of esophagus
  Esophageal cancer
  Multiple endocrine neoplasia type 1
  Acquired immune deficiency syndrome
  Adenoma
  Ductal breast carcinoma in situ
  Endometrial carcinoma
  Endometrium adenocarcinoma
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Germ cell tumor
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Human papillomavirus infection
  Kaposi sarcoma
  Laryngeal carcinoma
  Laryngeal squamous cell carcinoma
  Mucinous adenocarcinoma
  Mycosis fungoides
  Myelodysplastic syndrome
  Oral cancer
  Ovarian neoplasm
  Squamous cell carcinoma
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Urinary bladder neoplasm
  Usher syndrome
  Melanoma
  Neoplasm of esophagus
  Acute myelogenous leukaemia
  Breast neoplasm
  Carcinoid tumor
  Childhood kidney Wilms tumor
  Colorectal carcinoma
  Endometrial cancer
  Invasive breast carcinoma
  Myelofibrosis
  Nasopharyngeal carcinoma
  Ovarian cancer
  Primary myelofibrosis
  Vitelliform macular dystrophy
  Wilms tumor
• UniProt ID: INT2_HUMAN
• PDB ID: 7CUN; 7PKS; 7YCX
• Pfam ID: PF14750
• Sequence:
  MKDQQTVIMTECTSLQFVSPFAFEAMQKVDVVCLASLSDPELRLLLPCLVRMALCAPADQ
  SQSWAQDKKLILRLLSGVEAVNSIVALLSVDFHALEQDASKEQQLRHKLGGGSGESILVS
  QLQHGLTLEFEHSDSPRRLRLVLSELLAIMNKVSESNGEFFFKSSELFESPVYLEEAADV
  LCILQAELPSLLPIVDVAEALLHVRNGAWFLCLLVANVPDSFNEVCRGLIKNGERQDEES
  LGGRRRTDALRFLCKMNPSQALKVRGMVVEECHLPGLGVALTLDHTKNEACEDGVSDLVC
  FVSGLLLGTNAKVRTWFGTFIRNGQQRKRETSSSVLWQMRRQLLLELMGILPTVRSTRIV
  EEADVDMEPNVSVYSGLKEEHVVKASALLRLYCALMGIAGLKPTEEEAEQLLQLMTSRPP
  ATPAGVRFVSLSFCMLLAFSTLVSTPEQEQLMVVWLSWMIKEEAYFESTSGVSASFGEML
  LLVAMYFHSNQLSAIIDLVCSTLGMKIVIKPSSLSRMKTIFTQEIFTEQVVTAHAVRVPV
  TSNLSANITGFLPIHCIYQLLRSRSFTKHKVSIKDWIYRQLCETSTPLHPQLLPLIDVYI
  NSILTPASKSNPEATNQPVTEQEILNIFQGVIGGDNIRLNQRFSITAQLLVLYYILSYEE
  ALLANTKTLAAMQRKPKSYSSSLMDQIPIKFLIRQAQGLQQELGGLHSALLRLLATNYPH
  LCIVDDWICEEEITGTDALLRRMLLTNNAKNHSPKQLQEAFSAVPVNNTQVMQIIEHLTL
  LSASELIPYAEVLTSNMSQLLNSGVPRRILQTVNKLWMVLNTVMPRRLWVMTVNALQPSI
  KFVRQQKYTQNDLMIDPLIVLRCDQRVHRCPPLMDITLHMLNGYLLASKAYLSAHLKETE
  QDRPSQNNTIGLVGQTDAPEVTREELKNALLAAQDSAAVQILLEICLPTEEEKANGVNPD
  SLLRNVQSVITTSAPNKGMEEGEDNLLCNLREVQCLICCLLHQMYIADPNIAKLVHFQGY
  PCELLPLTVAGIPSMHICLDFIPELIAQPELEKQIFAIQLLSHLCIQYALPKSLSVARLA
  VNVMGTLLTVLTQAKRYAFFMPTLPSLVSFCRAFPPLYEDIMSLLIQIGQVCASDVATQT
  RDIDPIITRLQQIKEKPSGWSQICKDSSYKNGSRDTGSMDPDVQLCHCIERTVIEIINMS
  VSGI
• Function: Component of the Integrator (INT) complex, a complex involved in the small nuclear RNAs (snRNA) U1 and U2 transcription and in their 3'-box-dependent processing. The Integrator complex is associated with the C-terminal domain (CTD) of RNA polymerase II largest subunit (POLR2A) and is recruited to the U1 and U2 snRNAs genes (Probable). Mediates recruitment of cytoplasmic dynein to the nuclear envelope, probably as component of the INT complex.
• Reactome Pathway: RNA polymerase II transcribes snRNA genes (R-HSA-6807505)

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Carcinoma of esophagus	DISS6G4D	Definitive	Biomarker	[2]
Esophageal cancer	DISGB2VN	Definitive	Biomarker	[2]
Multiple endocrine neoplasia type 1	DIS0RJRK	Definitive	Biomarker	[3]
Acquired immune deficiency syndrome	DISL5UOX	Strong	Altered Expression	[4]
Adenoma	DIS78ZEV	Strong	Altered Expression	[5]
Ductal breast carcinoma in situ	DISLCJY7	Strong	Biomarker	[6]
Endometrial carcinoma	DISXR5CY	Strong	Genetic Variation	[7]
Endometrium adenocarcinoma	DISY6744	Strong	Biomarker	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[8]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[9]
Germ cell tumor	DIS62070	Strong	Altered Expression	[10]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[12]
Human papillomavirus infection	DISX61LX	Strong	Biomarker	[13]
Kaposi sarcoma	DISC1H1Z	Strong	Biomarker	[14]
Laryngeal carcinoma	DISNHCIV	Strong	Biomarker	[15]
Laryngeal squamous cell carcinoma	DIS9UUVF	Strong	Biomarker	[15]
Mucinous adenocarcinoma	DISKNFE8	Strong	Biomarker	[6]
Mycosis fungoides	DIS62RB8	Strong	Biomarker	[16]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[17]
Oral cancer	DISLD42D	Strong	Biomarker	[18]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[8]
Squamous cell carcinoma	DISQVIFL	Strong	Genetic Variation	[13]
Thyroid cancer	DIS3VLDH	Strong	Biomarker	[19]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[19]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[19]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[20]
Usher syndrome	DIS9YIS7	Strong	Genetic Variation	[21]
Melanoma	DIS1RRCY	moderate	Biomarker	[22]
Neoplasm of esophagus	DISOLKAQ	Disputed	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[23]
Breast neoplasm	DISNGJLM	Limited	Altered Expression	[24]
Carcinoid tumor	DISMNRDC	Limited	Biomarker	[1]
Childhood kidney Wilms tumor	DIS0NMK3	Limited	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Limited	Genetic Variation	[25]
Endometrial cancer	DISW0LMR	Limited	Genetic Variation	[26]
Invasive breast carcinoma	DISANYTW	Limited	Genetic Variation	[27]
Myelofibrosis	DISIMP21	Limited	Biomarker	[16]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[28]
Ovarian cancer	DISZJHAP	Limited	Genetic Variation	[29]
Primary myelofibrosis	DIS6L0CN	Limited	Biomarker	[16]
Vitelliform macular dystrophy	DISEFYYN	Limited	Genetic Variation	[30]
Wilms tumor	DISB6T16	Limited	Biomarker	[1]

11 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 Integrator complex subunit 2 (INTS2).	[31]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Integrator complex subunit 2 (INTS2).	[32]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Integrator complex subunit 2 (INTS2).	[33]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Integrator complex subunit 2 (INTS2).	[34]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Integrator complex subunit 2 (INTS2).	[35]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Integrator complex subunit 2 (INTS2).	[36]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Integrator complex subunit 2 (INTS2).	[37]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Integrator complex subunit 2 (INTS2).	[38]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Integrator complex subunit 2 (INTS2).	[39]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Integrator complex subunit 2 (INTS2).	[40]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR increases the expression of Integrator complex subunit 2 (INTS2).	[41]

References

• [1] 11q13 allelic imbalance discriminates pulmonary carcinoids from tumorlets. A microdissection-based genotyping approach useful in clinical practice.Am J Pathol. 1999 Aug;155(2):633-40. doi: 10.1016/S0002-9440(10)65159-0.
• [2] Gene amplification of int-2 and erbB in human esophageal cancer: relationship to clinicopathological variables.Cancer Invest. 1997;15(5):411-5. doi: 10.3109/07357909709047579.
• [3] Linkage analysis of 7 polymorphic markers at chromosome 11p11.2-11q13 in 27 multiple endocrine neoplasia type 1 families.Ann Hum Genet. 1993 Jan;57(1):17-25. doi: 10.1111/j.1469-1809.1993.tb00883.x.
• [4] Expression of int-2 oncogene in Kaposi's sarcoma lesions.J Clin Invest. 1993 Mar;91(3):1191-7. doi: 10.1172/JCI116279.
• [5] Molecular screening of pituitary adenomas for gene mutations and rearrangements.J Clin Endocrinol Metab. 1993 Jul;77(1):50-5. doi: 10.1210/jcem.77.1.8100831.
• [6] Detection of amplified int-2/FGF-3 gene in primary breast carcinomas using differential polymerase chain reaction.Int J Mol Med. 2001 Aug;8(2):193-8. doi: 10.3892/ijmm.8.2.193.
• [7] The coexistence of ERBB2, INT2, and CMYC oncogene amplifications and PTEN gene mutations in endometrial carcinoma.J Cancer Res Clin Oncol. 2004 Feb;130(2):114-21. doi: 10.1007/s00432-003-0518-7. Epub 2003 Dec 9.
• [8] Detection of c-erbB-2/neu and fibroblast growth factor-3/INT-2 but not epidermal growth factor receptor gene amplification in endometrial cancer by differential polymerase chain reaction.Cancer. 1995 Apr 15;75(8):2139-46. doi: 10.1002/1097-0142(19950415)75:8<2139::aid-cncr2820750817>3.0.co;2-6.
• [9] Inhibitory effects of Gleditsia sinensis fruit extract on telomerase activity and oncogenic expression in human esophageal squamous cell carcinoma.Int J Mol Med. 2007 Jun;19(6):953-60.
• [10] Expression of the hst-1 and c-kit protooncogenes in human testicular germ cell tumors.Cancer Res. 1991 Apr 1;51(7):1811-6.
• [11] Visualization of the timing of gene amplification during multistep head and neck tumorigenesis.Cancer Res. 2000 Nov 15;60(22):6496-502.
• [12] Amplification and overexpression of the cyclin D1 gene in aggressive human hepatocellular carcinoma.Cancer Res. 1994 Jun 15;54(12):3107-10.
• [13] First hints for a correlation between amplification of the Int-2 gene and infection with human papillomavirus in head and neck squamous cell carcinomas.J Oral Pathol Med. 2000 Oct;29(9):432-7. doi: 10.1034/j.1600-0714.2000.290903.x.
• [14] FGF4 and INT2 oncogenes are amplified and expressed in Kaposi's sarcoma.Mod Pathol. 2000 Apr;13(4):433-7. doi: 10.1038/modpathol.3880074.
• [15] Amplification of int-2 and bcl-1 genes in squamous cell carcinoma of the larynx.Acta Otolaryngol. 1998 Sep;118(5):763-8. doi: 10.1080/00016489850183331.
• [16] Genetically inspired prognostic scoring system (GIPSS) outperforms dynamic international prognostic scoring system (DIPSS) in myelofibrosis patients.Am J Hematol. 2019 Jan;94(1):87-92. doi: 10.1002/ajh.25335. Epub 2018 Nov 25.
• [17] MDS shows a higher expression of hTERT and alternative splice variants in unactivated T-cells.Oncotarget. 2016 Nov 1;7(44):71904-71914. doi: 10.18632/oncotarget.12115.
• [18] Inhibitory effects of int-2 gene on the invasion and metastasis of oral cancer cells.Eur Rev Med Pharmacol Sci. 2017 Dec;21(24):5677-5682. doi: 10.26355/eurrev_201712_14012.
• [19] INT-2 gene amplification in differentiated human thyroid cancer.Exp Clin Endocrinol Diabetes. 1996;104 Suppl 4:101-4. doi: 10.1055/s-0029-1211713.
• [20] Amplification of FGF-related genes in human tumors: possible involvement of HST in breast carcinomas.Oncogene. 1989 Jul;4(7):915-22.
• [21] Genetic mapping of the gene for Usher syndrome: linkage analysis in a large Samaritan kindred.Genomics. 1994 Mar 1;20(1):36-42. doi: 10.1006/geno.1994.1124.
• [22] Disruption of the protein interaction between FAK and IGF-1R inhibits melanoma tumor growth.Cell Cycle. 2012 Sep 1;11(17):3250-9. doi: 10.4161/cc.21611. Epub 2012 Aug 16.
• [23] International scoring system for evaluating prognosis in myelodysplastic syndromes.Blood. 1997 Mar 15;89(6):2079-88.
• [24] INT2 and ERBB2 amplification and ERBB2 expression in breast tumors from patients with different outcomes.Breast Cancer Res Treat. 1996;37(1):65-76. doi: 10.1007/BF01806633.
• [25] High incidence of coamplification of hst-1 and int-2 genes in human esophageal carcinomas.Cancer Res. 1989 Oct 15;49(20):5505-8.
• [26] Mutations and amplification of oncogenes in endometrial cancer.Oncology. 1999;56(1):59-65. doi: 10.1159/000011931.
• [27] Identical allelic loss on chromosome 11q13 in microdissected in situ and invasive human breast cancer.Cancer Res. 1995 Feb 1;55(3):467-71.
• [28] Frequent c-myc and Int-2 overrepresentations in nasopharyngeal carcinoma.Hum Pathol. 2000 Feb;31(2):169-78. doi: 10.1016/s0046-8177(00)80216-6.
• [29] Mutations in BRIP1 confer high risk of ovarian cancer.Nat Genet. 2011 Oct 2;43(11):1104-7. doi: 10.1038/ng.955.
• [30] Best's vitelliform dystrophy (VMD2) maps between D11S903 and PYGM: no evidence for locus heterogeneity.Genomics. 1994 Mar 15;20(2):267-74. doi: 10.1006/geno.1994.1163.
• [31] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [32] 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.
• [33] 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.
• [34] 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.
• [35] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [36] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [37] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [38] 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.
• [39] 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.
• [40] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [41] Gene expression network regulated by DNA methylation and microRNA during microcystin-leucine arginine induced malignant transformation in human hepatocyte L02 cells. Toxicol Lett. 2018 Jun 1;289:42-53. doi: 10.1016/j.toxlet.2018.03.003. Epub 2018 Mar 5.