Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSIJMQ9)

• DOT Name: Protein phosphatase 1 regulatory subunit 1B (PPP1R1B)
• Synonyms: DARPP-32; Dopamine- and cAMP-regulated neuronal phosphoprotein
• Gene Name: PPP1R1B
• Related Disease:
  Adenocarcinoma
  Esophageal squamous cell carcinoma
  Non-insulin dependent diabetes
  Adult glioblastoma
  Advanced cancer
  Alcohol dependence
  Alzheimer disease
  Autism
  Autism spectrum disorder
  Bipolar disorder
  Breast cancer
  Breast carcinoma
  Carcinoma
  Colorectal carcinoma
  Depression
  Drug dependence
  Gastric adenocarcinoma
  Glioblastoma multiforme
  Huntington disease
  Mood disorder
  Multiple system atrophy
  Neoplasm
  Nicotine dependence
  Opioid dependence
  Parkinson disease
  Parkinsonian disorder
  Squamous cell carcinoma
  Substance dependence
  Substance withdrawal syndrome
  Breast neoplasm
  Gastric neoplasm
  Small-cell lung cancer
  Spinocerebellar ataxia type 3
  Stroke
  HER2/NEU overexpressing breast cancer
  Growth delay due to insulin-like growth factor I resistance
  Movement disorder
  Psychotic disorder
  Status epilepticus seizure
  Stomach cancer
• UniProt ID: PPR1B_HUMAN
• Pfam ID: PF05395
• Sequence:
  MDPKDRKKIQFSVPAPPSQLDPRQVEMIRRRRPTPAMLFRLSEHSSPEEEASPHQRASGE
  GHHLKSKRPNPCAYTPPSLKAVQRIAESHLQSISNLNENQASEEEDELGELRELGYPREE
  DEEEEEDDEEEEEEEDSQAEVLKVIRQSAGQKTTCGQGLEGPWERPPPLDESERDGGSED
  QVEDPALSEPGEEPQRPSPSEPGT
• Function: Inhibitor of protein-phosphatase 1.
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Dopaminergic sy.pse (hsa04728)
  Cocaine addiction (hsa05030)
  Amphetamine addiction (hsa05031)
  Alcoholism (hsa05034)
• Reactome Pathway: DARPP-32 events (R-HSA-180024)

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Altered Expression	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Definitive	Biomarker	[2]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[3]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Biomarker	[6]
Autism	DISV4V1Z	Strong	Biomarker	[7]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[7]
Bipolar disorder	DISAM7J2	Strong	Altered Expression	[8]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[9]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[9]
Carcinoma	DISH9F1N	Strong	Biomarker	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[11]
Depression	DIS3XJ69	Strong	Biomarker	[12]
Drug dependence	DIS9IXRC	Strong	Biomarker	[13]
Gastric adenocarcinoma	DISWWLTC	Strong	Altered Expression	[14]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[4]
Huntington disease	DISQPLA4	Strong	Posttranslational Modification	[15]
Mood disorder	DISLVMWO	Strong	Altered Expression	[16]
Multiple system atrophy	DISASEYE	Strong	Biomarker	[17]
Neoplasm	DISZKGEW	Strong	Biomarker	[18]
Nicotine dependence	DISZD9W7	Strong	Biomarker	[19]
Opioid dependence	DIS6WEHK	Strong	Biomarker	[20]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[21]
Parkinsonian disorder	DISHGY45	Strong	Genetic Variation	[22]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[23]
Substance dependence	DISDRAAR	Strong	Biomarker	[24]
Substance withdrawal syndrome	DISTT24U	Strong	Altered Expression	[20]
Breast neoplasm	DISNGJLM	moderate	Biomarker	[25]
Gastric neoplasm	DISOKN4Y	moderate	Altered Expression	[26]
Small-cell lung cancer	DISK3LZD	moderate	Altered Expression	[27]
Spinocerebellar ataxia type 3	DISQBQID	moderate	Biomarker	[28]
Stroke	DISX6UHX	moderate	Biomarker	[29]
HER2/NEU overexpressing breast cancer	DISYKID5	Disputed	Biomarker	[30]
Growth delay due to insulin-like growth factor I resistance	DISWL710	Limited	Biomarker	[31]
Movement disorder	DISOJJ2D	Limited	Genetic Variation	[22]
Psychotic disorder	DIS4UQOT	Limited	Biomarker	[32]
Status epilepticus seizure	DISY3BIC	Limited	Biomarker	[33]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[34]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Protein phosphatase 1 regulatory subunit 1B (PPP1R1B) decreases the export of Doxorubicin.	[14]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Protein phosphatase 1 regulatory subunit 1B (PPP1R1B) increases the response to substance of Cisplatin.	[14]
Fluorouracil	DMUM7HZ	Approved	Protein phosphatase 1 regulatory subunit 1B (PPP1R1B) increases the response to substance of Fluorouracil.	[14]
Camptothecin	DM6CHNJ	Phase 3	Protein phosphatase 1 regulatory subunit 1B (PPP1R1B) decreases the response to substance of Camptothecin.	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein phosphatase 1 regulatory subunit 1B (PPP1R1B).	[35]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Protein phosphatase 1 regulatory subunit 1B (PPP1R1B).	[36]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Protein phosphatase 1 regulatory subunit 1B (PPP1R1B).	[37]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein phosphatase 1 regulatory subunit 1B (PPP1R1B).	[38]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Protein phosphatase 1 regulatory subunit 1B (PPP1R1B).	[35]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein phosphatase 1 regulatory subunit 1B (PPP1R1B).	[40]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein phosphatase 1 regulatory subunit 1B (PPP1R1B).	[41]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein phosphatase 1 regulatory subunit 1B (PPP1R1B).	[35]

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 decreases the methylation of Protein phosphatase 1 regulatory subunit 1B (PPP1R1B).	[39]

References

• [1] DARPP-32: from neurotransmission to cancer.Oncotarget. 2016 Apr 5;7(14):17631-40. doi: 10.18632/oncotarget.7268.
• [2] DRD2/DARPP-32 expression correlates with lymph node metastasis and tumor progression in patients with esophageal squamous cell carcinoma.World J Surg. 2006 Sep;30(9):1672-9; discussion 1680-1. doi: 10.1007/s00268-006-0035-3.
• [3] Interaction between prenatal pesticide exposure and a common polymorphism in the PON1 gene on DNA methylation in genes associated with cardio-metabolic disease risk-an exploratorystudy.Clin Epigenetics. 2017 Apr 5;9:35. doi: 10.1186/s13148-017-0336-4. eCollection 2017.
• [4] DARPP32, STAT5 and STAT3 mRNA expression ratios in glioblastomas are associated with patient outcome.Pathol Oncol Res. 2013 Apr;19(2):329-43. doi: 10.1007/s12253-012-9588-7. Epub 2012 Dec 20.
• [5] Motivational effects of ethanol in DARPP-32 knock-out mice.J Neurosci. 2001 Jan 1;21(1):340-8. doi: 10.1523/JNEUROSCI.21-01-00340.2001.
• [6] Identification of Electrophysiological Changes in Alzheimer's Disease: A Microarray Based Transcriptomics and Molecular Pathway Analysis Study.CNS Neurol Disord Drug Targets. 2017;16(9):1027-1038. doi: 10.2174/1871527316666171023153837.
• [7] DRD2 and PPP1R1B (DARPP-32) polymorphisms independently confer increased risk for autism spectrum disorders and additively predict affected status in male-only affected sib-pair families.Behav Brain Funct. 2012 May 4;8:19. doi: 10.1186/1744-9081-8-19.
• [8] Differential protein expression of DARPP-32 versus Calcineurin in the prefrontal cortex and nucleus accumbens in schizophrenia and bipolar disorder.Sci Rep. 2019 Oct 16;9(1):14877. doi: 10.1038/s41598-019-51456-7.
• [9] Darpp-32 and t-Darpp protein products of PPP1R1B: Old dogs with new tricks.Biochem Pharmacol. 2019 Feb;160:71-79. doi: 10.1016/j.bcp.2018.12.008. Epub 2018 Dec 12.
• [10] Darpp-32: a novel antiapoptotic gene in upper gastrointestinal carcinomas. Cancer Res. 2005 Aug 1;65(15):6583-92. doi: 10.1158/0008-5472.CAN-05-1433.
• [11] LncRNA KCNQ1OT1 enhanced the methotrexate resistance of colorectal cancer cells by regulating miR-760/PPP1R1B via the cAMP signalling pathway.J Cell Mol Med. 2019 Jun;23(6):3808-3823. doi: 10.1111/jcmm.14071. Epub 2019 Apr 17.
• [12] Cyclin-Dependent Kinase 5 Dysfunction Contributes to Depressive-like Behaviors in Huntington's Disease by Altering the DARPP-32 Phosphorylation Status in the Nucleus Accumbens.Biol Psychiatry. 2019 Aug 1;86(3):196-207. doi: 10.1016/j.biopsych.2019.03.001. Epub 2019 Mar 13.
• [13] Potential for targeting dopamine/DARPP-32 signaling in neuropsychiatric and neurodegenerative disorders.Expert Opin Ther Targets. 2017 Mar;21(3):259-272. doi: 10.1080/14728222.2017.1279149. Epub 2017 Jan 13.
• [14] Reversal of multidrug resistance of vincristine-resistant gastric adenocarcinoma cells through up-regulation of DARPP-32. Cell Biol Int. 2007 Sep;31(9):1010-5. doi: 10.1016/j.cellbi.2007.03.020. Epub 2007 Mar 21.
• [15] CTIP2-Regulated Reduction in PKA-Dependent DARPP32 Phosphorylation in Human Medium Spiny Neurons: Implications for Huntington Disease.Stem Cell Reports. 2019 Sep 10;13(3):448-457. doi: 10.1016/j.stemcr.2019.07.015. Epub 2019 Aug 22.
• [16] Revisiting DARPP-32 in postmortem human brain: changes in schizophrenia and bipolar disorder and genetic associations with t-DARPP-32 expression.Mol Psychiatry. 2014 Feb;19(2):192-9. doi: 10.1038/mp.2012.174. Epub 2013 Jan 8.
• [17] Anti-DARPP32 antibody-immunopositive inclusions in the brain of patients with multiple system atrophy.Clin Neuropathol. 2008 Sep-Oct;27(5):309-16. doi: 10.5414/npp27309.
• [18] Regulation of CD44E by DARPP-32-dependent activation of SRp20 splicing factor in gastric tumorigenesis.Oncogene. 2016 Apr 7;35(14):1847-56. doi: 10.1038/onc.2015.250. Epub 2015 Jun 29.
• [19] Association analysis of the protein phosphatase 1 regulatory subunit 1B (PPP1R1B) gene with nicotine dependence in European- and African-American smokers.Am J Med Genet B Neuropsychiatr Genet. 2007 Apr 5;144B(3):285-90. doi: 10.1002/ajmg.b.30399.
• [20] Nanotherapeutic approach for opiate addiction using DARPP-32 gene silencing in an animal model of opiate addiction.J Neuroimmune Pharmacol. 2015 Mar;10(1):136-52. doi: 10.1007/s11481-015-9585-1. Epub 2015 Jan 22.
• [21] Age affects reinforcement learning through dopamine-based learning imbalance and high decision noise-not through Parkinsonian mechanisms.Neurobiol Aging. 2018 Aug;68:102-113. doi: 10.1016/j.neurobiolaging.2018.04.006. Epub 2018 Apr 19.
• [22] Candidate gene-based association study of antipsychotic-induced movement disorders in long-stay psychiatric patients: a prospective study.PLoS One. 2012;7(5):e36561. doi: 10.1371/journal.pone.0036561. Epub 2012 May 15.
• [23] DARPP-32 expression arises after a phase of dysplasia in oesophageal squamous cell carcinoma.Br J Cancer. 2004 Jul 5;91(1):119-23. doi: 10.1038/sj.bjc.6601899.
• [24] Association study between casein kinase 1 epsilon gene and methamphetamine dependence.Ann N Y Acad Sci. 2008 Oct;1139:43-8. doi: 10.1196/annals.1432.025.
• [25] Darpp-32 and t-Darpp are differentially expressed in normal and malignant mouse mammary tissue.Mol Cancer. 2014 Aug 15;13:192. doi: 10.1186/1476-4598-13-192.
• [26] Reversal of multidrug resistance of adriamycin-resistant gastric adenocarcinoma cells through the up-regulation of DARPP-32.Dig Dis Sci. 2008 Jan;53(1):101-7. doi: 10.1007/s10620-007-9829-x. Epub 2007 May 11.
• [27] Genetic and Functional Analysis of Polymorphisms in the Human Dopamine Receptor and Transporter Genes in Small Cell Lung Cancer.J Cell Physiol. 2016 Feb;231(2):345-56. doi: 10.1002/jcp.25079.
• [28] Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease.Hum Mol Genet. 2008 Jul 15;17(14):2071-83. doi: 10.1093/hmg/ddn106. Epub 2008 Apr 1.
• [29] Contralaterally transplanted human embryonic stem cell-derived neural precursor cells (ENStem-A) migrate and improve brain functions in stroke-damaged rats.Exp Mol Med. 2013 Nov 15;45(11):e53. doi: 10.1038/emm.2013.93.
• [30] t-Darpp overexpression in HER2-positive breast cancer confers a survival advantage in lapatinib.Oncotarget. 2015 Oct 20;6(32):33134-45. doi: 10.18632/oncotarget.5311.
• [31] Activation of IGF1R by DARPP-32 promotes STAT3 signaling in gastric cancer cells.Oncogene. 2019 Jul;38(29):5805-5816. doi: 10.1038/s41388-019-0843-1. Epub 2019 Jun 24.
• [32] The mRNA Expression Status of Dopamine Receptor D2, Dopamine Receptor D3 and DARPP-32 in T Lymphocytes of Patients with Early Psychosis.Int J Mol Sci. 2015 Nov 6;16(11):26677-86. doi: 10.3390/ijms161125983.
• [33] [Research on expression and function of phosphorylated DARPP-32 on pentylenetetrazol-induced epilepsy model of rat].Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2014 Jun;31(3):637-41.
• [34] PPP1R1B-STARD3 chimeric fusion transcript in human gastric cancer promotes tumorigenesis through activation of PI3K/AKT signaling.Oncogene. 2014 Nov 13;33(46):5341-7. doi: 10.1038/onc.2013.472. Epub 2013 Nov 25.
• [35] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [36] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [37] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [38] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [39] 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.
• [40] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [41] 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.
• [42] Reversal of multidrug resistance of vincristine-resistant gastric adenocarcinoma cells through up-regulation of DARPP-32. Cell Biol Int. 2007 Sep;31(9):1010-5. doi: 10.1016/j.cellbi.2007.03.020. Epub 2007 Mar 21.
• [43] Darpp-32: a novel antiapoptotic gene in upper gastrointestinal carcinomas. Cancer Res. 2005 Aug 1;65(15):6583-92. doi: 10.1158/0008-5472.CAN-05-1433.