Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7UT2XB)

• DOT Name: Receptor activity-modifying protein 1 (RAMP1)
• Synonyms: Calcitonin-receptor-like receptor activity-modifying protein 1; CRLR activity-modifying protein 1
• Gene Name: RAMP1
• Related Disease:
  Arteriosclerosis
  Cerebral infarction
  Dysautonomia
  Myocardial infarction
  Stroke
  Asthma
  Carcinoma
  Colitis
  Essential hypertension
  Ewing sarcoma
  High blood pressure
  Pancreatitis
  Thyroid gland carcinoma
  Fetal growth restriction
  Neuroblastoma
  Prostate cancer
  Prostate carcinoma
• UniProt ID: RAMP1_HUMAN
• PDB ID: 2YX8; 3N7P; 3N7R; 3N7S; 4RWG; 5V6Y; 6D1U; 6E3Y; 6UMG; 6ZHO; 6ZIS; 7KNT; 7KNU; 7P0F; 7P0I; 7TYF; 7TYW; 8AX5; 8AX6; 8AX7
• Pfam ID: PF04901
• Sequence:
  MARALCRLPRRGLWLLLAHHLFMTTACQEANYGALLRELCLTQFQVDMEAVGETLWCDWG
  RTIRSYRELADCTWHMAEKLGCFWPNAEVDRFFLAVHGRYFRSCPISGRAVRDPPGSILY
  PFIVVPITVTLLVTALVVWQSKRTEGIV
• Function: Transports the calcitonin gene-related peptide type 1 receptor (CALCRL) to the plasma membrane. Acts as a receptor for calcitonin-gene-related peptide (CGRP) together with CALCRL.
• Tissue Specificity: Expressed in many tissues including the uterus, bladder, brain, pancreas and gastro-intestinal tract.
• KEGG Pathway: Vascular smooth muscle contraction (hsa04270)
• Reactome Pathway:
  Calcitonin-like ligand receptors (R-HSA-419812)
  G alpha (s) signalling events (R-HSA-418555)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Definitive	Altered Expression	[1]
Cerebral infarction	DISR1WNP	Definitive	Genetic Variation	[2]
Dysautonomia	DISF4MT6	Definitive	Biomarker	[3]
Myocardial infarction	DIS655KI	Definitive	Altered Expression	[1]
Stroke	DISX6UHX	Definitive	Altered Expression	[1]
Asthma	DISW9QNS	Strong	Biomarker	[4]
Carcinoma	DISH9F1N	Strong	Biomarker	[5]
Colitis	DISAF7DD	Strong	Biomarker	[6]
Essential hypertension	DIS7WI98	Strong	Biomarker	[7]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[8]
High blood pressure	DISY2OHH	Strong	Biomarker	[3]
Pancreatitis	DIS0IJEF	Strong	Biomarker	[9]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[10]
Fetal growth restriction	DIS5WEJ5	moderate	Altered Expression	[11]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[12]
Prostate cancer	DISF190Y	Disputed	Biomarker	[13]
Prostate carcinoma	DISMJPLE	Disputed	Biomarker	[13]

18 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 Receptor activity-modifying protein 1 (RAMP1).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Receptor activity-modifying protein 1 (RAMP1).	[15]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Receptor activity-modifying protein 1 (RAMP1).	[16]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Receptor activity-modifying protein 1 (RAMP1).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Receptor activity-modifying protein 1 (RAMP1).	[19]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Receptor activity-modifying protein 1 (RAMP1).	[20]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Receptor activity-modifying protein 1 (RAMP1).	[20]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Receptor activity-modifying protein 1 (RAMP1).	[21]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Receptor activity-modifying protein 1 (RAMP1).	[22]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Receptor activity-modifying protein 1 (RAMP1).	[23]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Receptor activity-modifying protein 1 (RAMP1).	[24]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Receptor activity-modifying protein 1 (RAMP1).	[25]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Receptor activity-modifying protein 1 (RAMP1).	[26]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Receptor activity-modifying protein 1 (RAMP1).	[27]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Receptor activity-modifying protein 1 (RAMP1).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Receptor activity-modifying protein 1 (RAMP1).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Receptor activity-modifying protein 1 (RAMP1).	[30]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Receptor activity-modifying protein 1 (RAMP1).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Receptor activity-modifying protein 1 (RAMP1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Receptor activity-modifying protein 1 (RAMP1).	[32]

References

• [1] Unaltered mRNA expression of calcitonin-like receptor and receptor activity modifying proteins in human arteries in stroke and myocardial infarction.Ideggyogy Sz. 2007 Nov 30;60(11-12):459-66.
• [2] Haplotype-based case-control study of receptor (calcitonin) activity-modifying protein-1 gene in cerebral infarction.J Hum Hypertens. 2010 May;24(5):351-8. doi: 10.1038/jhh.2009.68. Epub 2009 Aug 27.
• [3] Increased receptor activity-modifying protein 1 in the nervous system is sufficient to protect against autonomic dysregulation and hypertension.J Cereb Blood Flow Metab. 2019 Apr;39(4):690-703. doi: 10.1177/0271678X17751352. Epub 2018 Jan 3.
• [4] Deficiency of RAMP1 attenuates antigen-induced airway hyperresponsiveness in mice.PLoS One. 2014 Jul 10;9(7):e102356. doi: 10.1371/journal.pone.0102356. eCollection 2014.
• [5] Adrenomedullin (AM) and AM receptor type 2 expression is up-regulated in prostate carcinomas (PC), and AM stimulates in vitro growth of a PC-derived cell line by enhancing proliferation and decreasing apoptosis rates.Int J Oncol. 2004 Dec;25(6):1781-7.
• [6] RAMP1 suppresses mucosal injury from dextran sodium sulfate-induced colitis in mice.J Gastroenterol Hepatol. 2017 Apr;32(4):809-818. doi: 10.1111/jgh.13505.
• [7] Haplotype-based, case-control study of the receptor (calcitonin) activity-modifying protein (RAMP) 1 gene in essential hypertension.J Hum Hypertens. 2017 May;31(5):361-365. doi: 10.1038/jhh.2016.96. Epub 2017 Feb 9.
• [8] Targeting the CALCB/RAMP1 axis inhibits growth of Ewing sarcoma.Cell Death Dis. 2019 Feb 11;10(2):116. doi: 10.1038/s41419-019-1372-0.
• [9] The neuropeptide receptor subunit RAMP1 constrains the innate immune response during acute pancreatitis in mice.Pancreatology. 2019 Jun;19(4):541-547. doi: 10.1016/j.pan.2019.05.455. Epub 2019 May 11.
• [10] Role of receptor activity modifying protein 1 in function of the calcium sensing receptor in the human TT thyroid carcinoma cell line.PLoS One. 2014 Jan 13;9(1):e85237. doi: 10.1371/journal.pone.0085237. eCollection 2014.
• [11] Impaired Vasodilatory Responses of Omental Arteries to CGRP Family Peptides in Pregnancies Complicated by Fetal Growth Restriction.J Clin Endocrinol Metab. 2016 Aug;101(8):2984-93. doi: 10.1210/jc.2016-1798. Epub 2016 Jun 3.
• [12] Interaction of receptor-activity-modifying protein1 with tubulin.Biochim Biophys Acta. 2007 Aug;1770(8):1145-50. doi: 10.1016/j.bbagen.2007.04.002. Epub 2007 Apr 11.
• [13] RAMP1 is a direct NKX3.1 target gene up-regulated in prostate cancer that promotes tumorigenesis.Am J Pathol. 2013 Sep;183(3):951-63. doi: 10.1016/j.ajpath.2013.05.021. Epub 2013 Jul 16.
• [14] 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.
• [15] 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.
• [16] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [17] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [18] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [19] 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.
• [20] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [21] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [22] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [23] 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.
• [24] Dissecting progressive stages of 5-fluorouracil resistance in vitro using RNA expression profiling. Int J Cancer. 2004 Nov 1;112(2):200-12. doi: 10.1002/ijc.20401.
• [25] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [26] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [27] Comparative gene expression analysis of a chronic myelogenous leukemia cell line resistant to cyclophosphamide using oligonucleotide arrays and response to tyrosine kinase inhibitors. Leuk Res. 2007 Nov;31(11):1511-20.
• [28] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [29] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [30] 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.
• [31] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [32] 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.