Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR8QG5V)

• DOT Name: Retinol-binding protein 2 (RBP2)
• Synonyms: Cellular retinol-binding protein II; CRBP-II
• Gene Name: RBP2
• Related Disease:
  Breast cancer
  Malaria
  Bone osteosarcoma
  Breast carcinoma
  Carcinoma
  Carcinoma of esophagus
  Clear cell renal carcinoma
  Congestive heart failure
  Esophageal cancer
  Estrogen-receptor positive breast cancer
  Gastric cancer
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Immunodeficiency
  Medulloblastoma
  Melanoma
  Neoplasm of esophagus
  Non-small-cell lung cancer
  Osteosarcoma
  Pulmonary fibrosis
  Renal cell carcinoma
  Retinoblastoma
  Rheumatoid arthritis
  Stomach cancer
  Advanced cancer
  Astrocytoma
  Neoplasm
  Skin carcinoma
  Small-cell lung cancer
  Squamous cell carcinoma
  Atopic dermatitis
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Childhood kidney Wilms tumor
  Skin disease
  Thyroid gland carcinoma
  Thyroid gland papillary carcinoma
  Wilms tumor
• UniProt ID: RET2_HUMAN
• PDB ID: 2RCQ ; 2RCT ; 4EDE ; 4EEJ ; 4EFG ; 4EXZ ; 4GKC ; 4QYN ; 4QYP ; 4QZT ; 4QZU ; 4RUU ; 4ZCB ; 4ZGU ; 4ZH6 ; 4ZH9 ; 4ZJ0 ; 4ZR2 ; 5DG4 ; 5DPQ ; 5F58 ; 5F6B ; 5F7G ; 5FAZ ; 5FEN ; 5FFH ; 5U6G ; 6BTH ; 6BTI ; 6C7Z ; 6E50 ; 6E51 ; 6E5E ; 6E5Q ; 6E5R ; 6E5S ; 6E6L ; 6E7M ; 6MCU ; 6MCV ; 6MKV ; 6MLB ; 6ON5 ; 6ON7 ; 6ON8 ; 6VID ; 6VIS ; 6VIT ; 6WNF ; 6WNJ ; 6WP0 ; 6WP1 ; 6WP2 ; 7JVG ; 7JVY ; 7JWD ; 7JWR ; 7JX2 ; 7JZ5 ; 7K3I ; 7LHJ ; 7LHM ; 7LHN ; 7LHO ; 7LSQ ; 7MFX ; 7MFY ; 7MFZ ; 7UCN ; 7UCS ; 7UCT ; 7UCV ; 7UCZ ; 7UD1 ; 7UD3 ; 8D6H ; 8D6L ; 8D6N ; 8DB2 ; 8DN1
• Pfam ID: PF00061
• Sequence:
  MTRDQNGTWEMESNENFEGYMKALDIDFATRKIAVRLTQTKVIDQDGDNFKTKTTSTFRN
  YDVDFTVGVEFDEYTKSLDNRHVKALVTWEGDVLVCVQKGEKENRGWKQWIEGDKLYLEL
  TCGDQVCRQVFKKK
• Function: Intracellular transport of retinol.
• Tissue Specificity: Higher expression in adult small intestine and to a much lesser extent in fetal kidney.
• KEGG Pathway: Vitamin digestion and absorption (hsa04977)
• Reactome Pathway: Retinoid metabolism and transport (R-HSA-975634)
• BioCyc Pathway: MetaCyc:ENSG00000114113-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Malaria	DISQ9Y50	Definitive	Biomarker	[2]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Carcinoma	DISH9F1N	Strong	Biomarker	[4]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[6]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[7]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[5]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[1]
Gastric cancer	DISXGOUK	Strong	Biomarker	[8]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[10]
Immunodeficiency	DIS093I0	Strong	Altered Expression	[4]
Medulloblastoma	DISZD2ZL	Strong	Posttranslational Modification	[11]
Melanoma	DIS1RRCY	Strong	Altered Expression	[12]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[13]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[3]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[14]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[6]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[15]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[6]
Stomach cancer	DISKIJSX	Strong	Biomarker	[8]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[16]
Astrocytoma	DISL3V18	moderate	Altered Expression	[17]
Neoplasm	DISZKGEW	moderate	Altered Expression	[18]
Skin carcinoma	DISUZREN	moderate	Biomarker	[19]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[18]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[19]
Atopic dermatitis	DISTCP41	Limited	Biomarker	[20]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Limited	Altered Expression	[21]
Childhood kidney Wilms tumor	DIS0NMK3	Limited	Altered Expression	[22]
Skin disease	DISDW8R6	Limited	Altered Expression	[20]
Thyroid gland carcinoma	DISMNGZ0	Limited	Biomarker	[23]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Biomarker	[23]
Wilms tumor	DISB6T16	Limited	Altered Expression	[22]

4 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 Retinol-binding protein 2 (RBP2).	[24]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Retinol-binding protein 2 (RBP2).	[25]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Retinol-binding protein 2 (RBP2).	[26]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Retinol-binding protein 2 (RBP2).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Retinol-binding protein 2 (RBP2).	[27]

References

• [1] Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer.J Natl Cancer Inst. 2018 Apr 1;110(4). doi: 10.1093/jnci/djx207.
• [2] Characterization of Plasmodium ovale curtisi and P. ovale wallikeri in Western Kenya utilizing a novel species-specific real-time PCR assay.PLoS Negl Trop Dis. 2015 Jan 15;9(1):e0003469. doi: 10.1371/journal.pntd.0003469. eCollection 2015 Jan.
• [3] Competitive PCR demonstrates that 9-cis retinoic acid induces cellular retinoic acid-binding protein-II more efficiently than all-trans retinoic acid in human osteosarcoma cells.Biochem Biophys Res Commun. 1994 Apr 29;200(2):1125-9. doi: 10.1006/bbrc.1994.1567.
• [4] Mammary carcinoma suppression by cellular retinoic acid binding protein-II.Cancer Res. 2003 Aug 1;63(15):4426-33.
• [5] Retinoblastoma-binding protein 2 induces epithelial-mesenchymal transition in esophageal squamous cancer cells.Biotechnol Lett. 2015 Dec;37(12):2365-70. doi: 10.1007/s10529-015-1925-y. Epub 2015 Aug 12.
• [6] Expression and functional influence of cellular retinoic acid-binding protein II in renal cell carcinoma.Urol Int. 2005;75(3):269-76. doi: 10.1159/000087807.
• [7] Identification of circulating placental mRNA in maternal blood of pregnancies affected with fetal congenital heart diseases at the second trimester of pregnancy: implications for early molecular screening.Prenat Diagn. 2010 Mar;30(3):229-34. doi: 10.1002/pd.2443.
• [8] Critical role of histone demethylase RBP2 in human gastric cancer angiogenesis.Mol Cancer. 2014 Apr 9;13:81. doi: 10.1186/1476-4598-13-81.
• [9] Transcriptional regulation of retinoic acid responsive genes by cellular retinoic acid binding protein-II modulates RA mediated tumor cell proliferation and invasion.Anticancer Res. 1998 Jan-Feb;18(1A):217-24.
• [10] High Expression of Retinoblastoma-Binding Protein 2 (RBP2) in Patients with Hepatocellular Carcinoma and Its Prognostic Significance.Med Sci Monit. 2017 Jun 5;23:2736-2744. doi: 10.12659/msm.905262.
• [11] CRABP-II methylation: a critical determinant of retinoic acid resistance of medulloblastoma cells.Mol Oncol. 2012 Feb;6(1):48-61. doi: 10.1016/j.molonc.2011.11.004. Epub 2011 Nov 25.
• [12] Vitamin A metabolism and mRNA expression of retinoid-binding protein and receptor genes in human epidermal melanocytes and melanoma cells.Melanoma Res. 1997 Aug;7(4):267-74. doi: 10.1097/00008390-199708000-00001.
• [13] RBP2 induces epithelial-mesenchymal transition in non-small cell lung cancer.PLoS One. 2013 Dec 20;8(12):e84735. doi: 10.1371/journal.pone.0084735. eCollection 2013.
• [14] Hypocrea peltata: a mycological Dr Jekyll and Mr Hyde?.Mycologia. 2011 May-Jun;103(3):616-30. doi: 10.3852/10-227. Epub 2011 Jan 24.
• [15] Bdp, a new member of a family of DNA-binding proteins, associates with the retinoblastoma gene product.Cancer Res. 1999 Aug 1;59(15):3741-7.
• [16] Autochthonous tumors driven by Rb1 loss have an ongoing requirement for the RBP2 histone demethylase.Proc Natl Acad Sci U S A. 2018 Apr 17;115(16):E3741-E3748. doi: 10.1073/pnas.1716029115. Epub 2018 Apr 2.
• [17] CRABP-II- and FABP5-independent responsiveness of human glioblastoma cells to all-trans retinoic acid.Oncotarget. 2015 Mar 20;6(8):5889-902. doi: 10.18632/oncotarget.3334.
• [18] The KDM5A/RBP2 histone demethylase represses NOTCH signaling to sustain neuroendocrine differentiation and promote small cell lung cancer tumorigenesis.Genes Dev. 2019 Dec 1;33(23-24):1718-1738. doi: 10.1101/gad.328336.119. Epub 2019 Nov 14.
• [19] Loss of CRABP-II Characterizes Human Skin Poorly Differentiated Squamous Cell Carcinomas and Favors DMBA/TPA-Induced Carcinogenesis.J Invest Dermatol. 2016 Jun;136(6):1255-1266. doi: 10.1016/j.jid.2016.01.039. Epub 2016 Mar 2.
• [20] Differential expression of CRABP II, psoriasin and cytokeratin 1 mRNA in human skin diseases.Arch Dermatol Res. 1996 Jul;288(8):426-30. doi: 10.1007/BF02505229.
• [21] Histone demethylase RBP2 mediates the blast crisis of chronic myeloid leukemia through an RBP2/PTEN/BCR-ABL cascade.Cell Signal. 2019 Nov;63:109360. doi: 10.1016/j.cellsig.2019.109360. Epub 2019 Jul 30.
• [22] Regulation of CRABP-II expression by MycN in Wilms tumor.Exp Cell Res. 2008 Dec 10;314(20):3663-8. doi: 10.1016/j.yexcr.2008.09.029. Epub 2008 Oct 14.
• [23] Immunohistochemical expression of RBP2 and LSD1 in papillary thyroid carcinoma.Rom J Morphol Embryol. 2013;54(3):499-503.
• [24] Intestinal absorption of vitamins. Curr Opin Gastroenterol. 1999 Mar;15(2):172-6. doi: 10.1097/00001574-199903000-00015.
• [25] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [26] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [27] 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.
• [28] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.