Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC88VQO)

• DOT Name: Apoptosis-stimulating of p53 protein 1 (PPP1R13B)
• Synonyms: Protein phosphatase 1 regulatory subunit 13B
• Gene Name: PPP1R13B
• Related Disease:
  Acute myelogenous leukaemia
  Adenocarcinoma
  Adult glioblastoma
  Breast cancer
  Childhood acute lymphoblastic leukemia
  Chronic myelomonocytic leukaemia
  Classic Hodgkin lymphoma
  Colon cancer
  Colon carcinoma
  Gestational trophoblastic neoplasia
  Glioblastoma multiforme
  Head and neck cancer
  Head and neck carcinoma
  Hepatitis B virus infection
  Hepatocellular carcinoma
  HIV infectious disease
  Lung cancer
  Lung carcinoma
  Lymphoproliferative syndrome
  Malignant glioma
  Mood disorder
  Nasopharyngeal carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Plasma cell myeloma
  Pneumococcal meningitis
  Polycythemia
  Primary familial polycythemia due to EPO receptor mutation
  Pulmonary fibrosis
  Rabies
  Schizophrenia
  Thymus lymphoma
  Breast carcinoma
  Choriocarcinoma
  Colorectal carcinoma
  Hydatidiform mole
  Kidney cancer
  Prostate cancer
  Prostate carcinoma
  Renal carcinoma
  Renal cell carcinoma
  Small lymphocytic lymphoma
  Acute lymphocytic leukaemia
  Advanced cancer
  Clear cell renal carcinoma
  Hepatitis C virus infection
  Mesothelioma
• UniProt ID: ASPP1_HUMAN
• PDB ID: 6HL5
• Pfam ID: PF12796 ; PF21801 ; PF00018
• Sequence:
  MMPMILTVFLSNNEQILTEVPITPETTCRDVVEFCKEPGEGSCHLAEVWRGNERPIPFDH
  MMYEHLQKWGPRREEVKFFLRHEDSPTENSEQGGRQTQEQRTQRNVINVPGEKRTENGVG
  NPRVELTLSELQDMAARQQQQIENQQQMLVAKEQRLHFLKQQERRQQQSISENEKLQKLK
  ERVEAQENKLKKIRAMRGQVDYSKIMNGNLSAEIERFSAMFQEKKQEVQTAILRVDQLSQ
  QLEDLKKGKLNGFQSYNGKLTGPAAVELKRLYQELQIRNQLNQEQNSKLQQQKELLNKRN
  MEVAMMDKRISELRERLYGKKIQLNRVNGTSSPQSPLSTSGRVAAVGPYIQVPSAGSFPV
  LGDPIKPQSLSIASNAAHGRSKSANDGNWPTLKQNSSSSVKPVQVAGADWKDPSVEGSVK
  QGTVSSQPVPFSALGPTEKPGIEIGKVPPPIPGVGKQLPPSYGTYPSPTPLGPGSTSSLE
  RRKEGSLPRPSAGLPSRQRPTLLPATGSTPQPGSSQQIQQRISVPPSPTYPPAGPPAFPA
  GDSKPELPLTVAIRPFLADKGSRPQSPRKGPQTVNSSSIYSMYLQQATPPKNYQPAAHSA
  LNKSVKAVYGKPVLPSGSTSPSPLPFLHGSLSTGTPQPQPPSESTEKEPEQDGPAAPADG
  STVESLPRPLSPTKLTPIVHSPLRYQSDADLEALRRKLANAPRPLKKRSSITEPEGPGGP
  NIQKLLYQRFNTLAGGMEGTPFYQPSPSQDFMGTLADVDNGNTNANGNLEELPPAQPTAP
  LPAEPAPSSDANDNELPSPEPEELICPQTTHQTAEPAEDNNNNVATVPTTEQIPSPVAEA
  PSPGEEQVPPAPLPPASHPPATSTNKRTNLKKPNSERTGHGLRVRFNPLALLLDASLEGE
  FDLVQRIIYEVEDPSKPNDEGITPLHNAVCAGHHHIVKFLLDFGVNVNAADSDGWTPLHC
  AASCNSVHLCKQLVESGAAIFASTISDIETAADKCEEMEEGYIQCSQFLYGVQEKLGVMN
  KGVAYALWDYEAQNSDELSFHEGDALTILRRKDESETEWWWARLGDREGYVPKNLLGLYP
  RIKPRQRTLA
• Function: Regulator that plays a central role in regulation of apoptosis via its interaction with p53/TP53. Regulates TP53 by enhancing the DNA binding and transactivation function of TP53 on the promoters of proapoptotic genes in vivo.
• Tissue Specificity: Reduced expression in breast carcinomas expressing a wild-type TP53 protein.
• Reactome Pathway:
  TP53 Regulates Transcription of Genes Involved in Cytochrome C Release (R-HSA-6803204)
  TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain (R-HSA-6803205)
  TP53 Regulates Transcription of Death Receptors and Ligands (R-HSA-6803211)
  Regulation of TP53 Activity through Association with Co-factors (R-HSA-6804759)
  Activation of PUMA and translocation to mitochondria (R-HSA-139915)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[5]
Chronic myelomonocytic leukaemia	DISDN5P7	Strong	Genetic Variation	[6]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Altered Expression	[7]
Colon cancer	DISVC52G	Strong	Biomarker	[8]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[8]
Gestational trophoblastic neoplasia	DIS4EJNA	Strong	Biomarker	[9]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[10]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[10]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Posttranslational Modification	[11]
HIV infectious disease	DISO97HC	Strong	Biomarker	[12]
Lung cancer	DISCM4YA	Strong	Biomarker	[2]
Lung carcinoma	DISTR26C	Strong	Biomarker	[2]
Lymphoproliferative syndrome	DISMVL8O	Strong	Biomarker	[7]
Malignant glioma	DISFXKOV	Strong	Biomarker	[13]
Mood disorder	DISLVMWO	Strong	Biomarker	[14]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Biomarker	[15]
Neoplasm	DISZKGEW	Strong	Biomarker	[16]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[17]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[18]
Pneumococcal meningitis	DISM5U0L	Strong	Biomarker	[19]
Polycythemia	DIS8B6VW	Strong	Genetic Variation	[20]
Primary familial polycythemia due to EPO receptor mutation	DISFVI97	Strong	Biomarker	[20]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[21]
Rabies	DISSC4V5	Strong	Biomarker	[19]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[22]
Thymus lymphoma	DISJ17C5	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[4]
Choriocarcinoma	DISDBVNL	moderate	Altered Expression	[23]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[24]
Hydatidiform mole	DISKNP7O	moderate	Biomarker	[23]
Kidney cancer	DISBIPKM	moderate	Altered Expression	[25]
Prostate cancer	DISF190Y	moderate	Altered Expression	[26]
Prostate carcinoma	DISMJPLE	moderate	Altered Expression	[26]
Renal carcinoma	DISER9XT	moderate	Altered Expression	[25]
Renal cell carcinoma	DISQZ2X8	moderate	Biomarker	[25]
Small lymphocytic lymphoma	DIS30POX	moderate	Genetic Variation	[27]
Acute lymphocytic leukaemia	DISPX75S	Disputed	Biomarker	[1]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[28]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[25]
Hepatitis C virus infection	DISQ0M8R	Limited	Biomarker	[29]
Mesothelioma	DISKWK9M	Limited	Altered Expression	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Apoptosis-stimulating of p53 protein 1 (PPP1R13B).	[31]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Apoptosis-stimulating of p53 protein 1 (PPP1R13B).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Apoptosis-stimulating of p53 protein 1 (PPP1R13B).	[41]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Apoptosis-stimulating of p53 protein 1 (PPP1R13B).	[44]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Apoptosis-stimulating of p53 protein 1 (PPP1R13B).	[45]

10 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 Apoptosis-stimulating of p53 protein 1 (PPP1R13B).	[32]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Apoptosis-stimulating of p53 protein 1 (PPP1R13B).	[33]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Apoptosis-stimulating of p53 protein 1 (PPP1R13B).	[34]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Apoptosis-stimulating of p53 protein 1 (PPP1R13B).	[35]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Apoptosis-stimulating of p53 protein 1 (PPP1R13B).	[37]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Apoptosis-stimulating of p53 protein 1 (PPP1R13B).	[38]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Apoptosis-stimulating of p53 protein 1 (PPP1R13B).	[39]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Apoptosis-stimulating of p53 protein 1 (PPP1R13B).	[40]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Apoptosis-stimulating of p53 protein 1 (PPP1R13B).	[42]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Apoptosis-stimulating of p53 protein 1 (PPP1R13B).	[43]

References

• [1] Significance of Inactivated Genes in Leukemia: Pathogenesis and Prognosis.Cell J. 2017 Spring;19(Suppl 1):9-26. doi: 10.22074/cellj.2017.4908. Epub 2017 May 17.
• [2] Clinical and histopathologic evaluation of the expression of Ha-ras and fes oncogene products in lung cancer.Cancer. 1992 Mar 1;69(5):1130-6. doi: 10.1002/cncr.2820690512.
• [3] Yes and PI3K bind CD95 to signal invasion of glioblastoma.Cancer Cell. 2008 Mar;13(3):235-48. doi: 10.1016/j.ccr.2008.02.003.
• [4] Hyaluronic acid decorated pluronic P85 solid lipid nanoparticles as a potential carrier to overcome multidrug resistance in cervical and breast cancer.Biomed Pharmacother. 2017 Feb;86:595-604. doi: 10.1016/j.biopha.2016.12.041. Epub 2016 Dec 24.
• [5] ASPP1, a common activator of TP53, is inactivated by aberrant methylation of its promoter in acute lymphoblastic leukemia.Oncogene. 2006 Mar 23;25(13):1862-70. doi: 10.1038/sj.onc.1209236.
• [6] Juvenile myelomonocytic leukaemia-associated mutation in Cbl promotes resistance to apoptosis via the Lyn-PI3K/AKT pathway.Oncogene. 2015 Feb 5;34(6):789-97. doi: 10.1038/onc.2013.596. Epub 2014 Jan 27.
• [7] Expression of a mutated form of the p85alpha regulatory subunit of phosphatidylinositol 3-kinase in a Hodgkin's lymphoma-derived cell line (CO).Leukemia. 2002 May;16(5):894-901. doi: 10.1038/sj.leu.2402484.
• [8] Inhibition of Growth and Metastasis of Colon Cancer by Delivering 5-Fluorouracil-loaded Pluronic P85 Copolymer Micelles.Sci Rep. 2016 Feb 11;6:20896. doi: 10.1038/srep20896.
• [9] Overexpression of iASPP is required for autophagy in response to oxidative stress in choriocarcinoma.BMC Cancer. 2019 Oct 15;19(1):953. doi: 10.1186/s12885-019-6206-z.
• [10] Phosphorylation of PI3K regulatory subunit p85 contributes to resistance against PI3K inhibitors in radioresistant head and neck cancer.Oral Oncol. 2018 Mar;78:56-63. doi: 10.1016/j.oraloncology.2018.01.014. Epub 2018 Feb 20.
• [11] Epigenetic silence of ankyrin-repeat-containing, SH3-domain-containing, and proline-rich-region- containing protein 1 (ASPP1) and ASPP2 genes promotes tumor growth in hepatitis B virus-positive hepatocellular carcinoma.Hepatology. 2010 Jan;51(1):142-53. doi: 10.1002/hep.23247.
• [12] Tim-3 is a Marker of Plasmacytoid Dendritic Cell Dysfunction during HIV Infection and Is Associated with the Recruitment of IRF7 and p85 into Lysosomes and with the Submembrane Displacement of TLR9.J Immunol. 2017 Apr 15;198(8):3181-3194. doi: 10.4049/jimmunol.1601298. Epub 2017 Mar 6.
• [13] Loss of merlin-p85 protein complex in NF2-related tumors.Int J Oncol. 1998 May;12(5):1073-8. doi: 10.3892/ijo.12.5.1073.
• [14] Abnormal G protein alpha(s) - and alpha(i2)-subunit mRNA expression in bipolar affective disorder.Mol Psychiatry. 1998 Nov;3(6):512-20. doi: 10.1038/sj.mp.4000393.
• [15] LZTS2 inhibits PI3K/AKT activation and radioresistance in nasopharyngeal carcinoma by interacting with p85.Cancer Lett. 2018 Apr 28;420:38-48. doi: 10.1016/j.canlet.2018.01.067. Epub 2018 Jan 31.
• [16] The p85 isoform of the kinase S6K1 functions as a secreted oncoprotein to facilitate cell migration and tumor growth.Sci Signal. 2018 Mar 27;11(523):eaao1052. doi: 10.1126/scisignal.aao1052.
• [17] MiR-503 targets PI3K p85 and IKK- and suppresses progression of non-small cell lung cancer.Int J Cancer. 2014 Oct 1;135(7):1531-42. doi: 10.1002/ijc.28799. Epub 2014 Mar 27.
• [18] A novel interaction between fibroblast growth factor receptor 3 and the p85 subunit of phosphoinositide 3-kinase: activation-dependent regulation of ERK by p85 in multiple myeloma cells.Hum Mol Genet. 2009 Jun 1;18(11):1951-61. doi: 10.1093/hmg/ddp116. Epub 2009 Mar 13.
• [19] Brain-targeted delivery of PEGylated nano-bacitracin A against Penicillin-sensitive and -resistant Pneumococcal meningitis: formulated with RVG(29) and Pluronic() P85 unimers.Drug Deliv. 2018 Nov;25(1):1886-1897. doi: 10.1080/10717544.2018.1486473.
• [20] Ligand-induced EpoR internalization is mediated by JAK2 and p85 and is impaired by mutations responsible for primary familial and congenital polycythemia.Blood. 2009 May 21;113(21):5287-97. doi: 10.1182/blood-2008-09-179572. Epub 2009 Mar 31.
• [21] CircRNA-012091/PPP1R13B-mediated Lung Fibrotic Response in Silicosis via Endoplasmic Reticulum Stress and Autophagy.Am J Respir Cell Mol Biol. 2019 Sep;61(3):380-391. doi: 10.1165/rcmb.2019-0017OC.
• [22] Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.Mol Autism. 2017 May 22;8:21. doi: 10.1186/s13229-017-0137-9. eCollection 2017.
• [23] Downregulation of ASPP1 in gestational trophoblastic disease: correlation with hypermethylation, apoptotic activity and clinical outcome.Mod Pathol. 2011 Apr;24(4):522-32. doi: 10.1038/modpathol.2010.216. Epub 2010 Nov 19.
• [24] DC-SIGN-LEF1/TCF1-miR-185 feedback loop promotes colorectal cancer invasion and metastasis.Cell Death Differ. 2020 Jan;27(1):379-395. doi: 10.1038/s41418-019-0361-2. Epub 2019 Jun 19.
• [25] Anticancer activity of Schiff base-Poloxamer P85 combination against kidney cancer.Int Urol Nephrol. 2018 Feb;50(2):247-255. doi: 10.1007/s11255-017-1782-9. Epub 2017 Dec 29.
• [26] LSD1 Activates PI3K/AKT Signaling Through Regulating p85 Expression in Prostate Cancer Cells.Front Oncol. 2019 Aug 2;9:721. doi: 10.3389/fonc.2019.00721. eCollection 2019.
• [27] Integrative genomic analysis implicates gain of PIK3CA at 3q26 and MYC at 8q24 in chronic lymphocytic leukemia.Clin Cancer Res. 2012 Jul 15;18(14):3791-802. doi: 10.1158/1078-0432.CCR-11-2342. Epub 2012 May 23.
• [28] Molecular Mechanisms of Human Disease Mediated by Oncogenic and Primary Immunodeficiency Mutations in Class IA Phosphoinositide 3-Kinases.Front Immunol. 2018 Mar 19;9:575. doi: 10.3389/fimmu.2018.00575. eCollection 2018.
• [29] Hepatitis C virus NS5A protein interacts with beta-catenin and stimulates its transcriptional activity in a phosphoinositide-3 kinase-dependent fashion.J Gen Virol. 2010 Feb;91(Pt 2):373-81. doi: 10.1099/vir.0.015305-0. Epub 2009 Oct 21.
• [30] Reduced cell viability and apoptosis induction in human thyroid carcinoma and mesothelioma cells exposed to cidofovir.Toxicol In Vitro. 2017 Jun;41:49-55. doi: 10.1016/j.tiv.2017.02.008. Epub 2017 Feb 20.
• [31] 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.
• [32] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [33] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [36] 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.
• [37] 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.
• [38] Aberrantly expressed genes in HaCaT keratinocytes chronically exposed to arsenic trioxide. Biomark Insights. 2011 Feb 8;6:7-16.
• [39] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [40] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [41] 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.
• [42] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [43] 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.
• [44] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [45] 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.