Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOWJ2Y4)

• DOT Name: Apoptosis-stimulating of p53 protein 2 (TP53BP2)
• Synonyms: Bcl2-binding protein; Bbp; Renal carcinoma antigen NY-REN-51; Tumor suppressor p53-binding protein 2; 53BP2; p53-binding protein 2; p53BP2
• Gene Name: TP53BP2
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Breast lobular carcinoma
  Breast neoplasm
  Esophageal squamous cell carcinoma
  Gestational trophoblastic neoplasia
  Hepatitis B virus infection
  Immunodeficiency
  Lung cancer
  Lung carcinoma
  Metastatic malignant neoplasm
  Neoplasm
  Neuroblastoma
  Non-small-cell lung cancer
  Squamous cell carcinoma
  Choriocarcinoma
  Colorectal carcinoma
  Gastric cancer
  Hydatidiform mole
  Laryngeal squamous cell carcinoma
  Stomach cancer
  Gastric neoplasm
  Acute leukaemia
  Adult lymphoma
  B-cell lymphoma
  Gallbladder cancer
  Gallbladder carcinoma
  leukaemia
  Leukemia
  Lymphoid leukemia
  Lymphoma
  OPTN-related open angle glaucoma
  Osteomyelitis
  Pediatric lymphoma
  Proliferative vitreoretinopathy
  Tourette syndrome
• UniProt ID: ASPP2_HUMAN
• PDB ID: 1YCS; 2UWQ; 4A63; 4IRV; 6GHM; 6HKP
• Pfam ID: PF12796 ; PF21801 ; PF00018
• Sequence:
  MMPMFLTVYLSNNEQHFTEVPVTPETICRDVVDLCKEPGESDCHLAEVWCGSERPVADNE
  RMFDVLQRFGSQRNEVRFFLRHERPPGRDIVSGPRSQDPSLKRNGVKVPGEYRRKENGVN
  SPRMDLTLAELQEMASRQQQQIEAQQQLLATKEQRLKFLKQQDQRQQQQVAEQEKLKRLK
  EIAENQEAKLKKVRALKGHVEQKRLSNGKLVEEIEQMNNLFQQKQRELVLAVSKVEELTR
  QLEMLKNGRIDSHHDNQSAVAELDRLYKELQLRNKLNQEQNAKLQQQRECLNKRNSEVAV
  MDKRVNELRDRLWKKKAALQQKENLPVSSDGNLPQQAASAPSRVAAVGPYIQSSTMPRMP
  SRPELLVKPALPDGSLVIQASEGPMKIQTLPNMRSGAASQTKGSKIHPVGPDWSPSNADL
  FPSQGSASVPQSTGNALDQVDDGEVPLREKEKKVRPFSMFDAVDQSNAPPSFGTLRKNQS
  SEDILRDAQVANKNVAKVPPPVPTKPKQINLPYFGQTNQPPSDIKPDGSSQQLSTVVPSM
  GTKPKPAGQQPRVLLSPSIPSVGQDQTLSPGSKQESPPAAAVRPFTPQPSKDTLLPPFRK
  PQTVAASSIYSMYTQQQAPGKNFQQAVQSALTKTHTRGPHFSSVYGKPVIAAAQNQQQHP
  ENIYSNSQGKPGSPEPETEPVSSVQENHENERIPRPLSPTKLLPFLSNPYRNQSDADLEA
  LRKKLSNAPRPLKKRSSITEPEGPNGPNIQKLLYQRTTIAAMETISVPSYPSKSASVTAS
  SESPVEIQNPYLHVEPEKEVVSLVPESLSPEDVGNASTENSDMPAPSPGLDYEPEGVPDN
  SPNLQNNPEEPNPEAPHVLDVYLEEYPPYPPPPYPSGEPEGPGEDSVSMRPPEITGQVSL
  PPGKRTNLRKTGSERIAHGMRVKFNPLALLLDSSLEGEFDLVQRIIYEVDDPSLPNDEGI
  TALHNAVCAGHTEIVKFLVQFGVNVNAADSDGWTPLHCAASCNNVQVCKFLVESGAAVFA
  MTYSDMQTAADKCEEMEEGYTQCSQFLYGVQEKMGIMNKGVIYALWDYEPQNDDELPMKE
  GDCMTIIHREDEDEIEWWWARLNDKEGYVPRNLLGLYPRIKPRQRSLA
• Function: Regulator that plays a central role in regulation of apoptosis and cell growth via its interactions with proteins such as TP53. Regulates TP53 by enhancing the DNA binding and transactivation function of TP53 on the promoters of proapoptotic genes in vivo. Inhibits the ability of NAE1 to conjugate NEDD8 to CUL1, and thereby decreases NAE1 ability to induce apoptosis. Impedes cell cycle progression at G2/M. Its apoptosis-stimulating activity is inhibited by its interaction with DDX42.
• Tissue Specificity: Widely expressed. Expressed in spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocyte. Reduced expression in breast carcinomas expressing a wild-type TP53 protein. Overexpressed in lung cancer cell lines.
• KEGG Pathway: Hippo sig.ling pathway (hsa04390)
• 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

38 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Breast lobular carcinoma	DISBY98Q	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[5]
Gestational trophoblastic neoplasia	DIS4EJNA	Strong	Biomarker	[6]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[7]
Immunodeficiency	DIS093I0	Strong	Altered Expression	[8]
Lung cancer	DISCM4YA	Strong	Biomarker	[9]
Lung carcinoma	DISTR26C	Strong	Biomarker	[9]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[10]
Neoplasm	DISZKGEW	Strong	Altered Expression	[11]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[12]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[13]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[10]
Choriocarcinoma	DISDBVNL	moderate	Biomarker	[14]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[15]
Gastric cancer	DISXGOUK	moderate	Biomarker	[16]
Hydatidiform mole	DISKNP7O	moderate	Altered Expression	[14]
Laryngeal squamous cell carcinoma	DIS9UUVF	moderate	Biomarker	[17]
Stomach cancer	DISKIJSX	moderate	Biomarker	[16]
Gastric neoplasm	DISOKN4Y	Disputed	Genetic Variation	[18]
Acute leukaemia	DISDQFDI	Limited	Altered Expression	[19]
Adult lymphoma	DISK8IZR	Limited	Altered Expression	[20]
B-cell lymphoma	DISIH1YQ	Limited	Altered Expression	[20]
Gallbladder cancer	DISXJUAF	Limited	Altered Expression	[21]
Gallbladder carcinoma	DISD6ACL	Limited	Altered Expression	[21]
leukaemia	DISS7D1V	Limited	Altered Expression	[19]
Leukemia	DISNAKFL	Limited	Altered Expression	[19]
Lymphoid leukemia	DIS65TYQ	Limited	Altered Expression	[19]
Lymphoma	DISN6V4S	Limited	Altered Expression	[20]
OPTN-related open angle glaucoma	DISDR98A	Limited	Biomarker	[22]
Osteomyelitis	DIS0VUZL	Limited	Biomarker	[23]
Pediatric lymphoma	DIS51BK2	Limited	Altered Expression	[20]
Proliferative vitreoretinopathy	DISZTEK1	Limited	Altered Expression	[24]
Tourette syndrome	DISX9D54	No Known	Unknown	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Apoptosis-stimulating of p53 protein 2 (TP53BP2).	[26]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Apoptosis-stimulating of p53 protein 2 (TP53BP2).	[27]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Apoptosis-stimulating of p53 protein 2 (TP53BP2).	[28]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Apoptosis-stimulating of p53 protein 2 (TP53BP2).	[27]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Apoptosis-stimulating of p53 protein 2 (TP53BP2).	[29]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Apoptosis-stimulating of p53 protein 2 (TP53BP2).	[30]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Apoptosis-stimulating of p53 protein 2 (TP53BP2).	[31]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Apoptosis-stimulating of p53 protein 2 (TP53BP2).	[32]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Apoptosis-stimulating of p53 protein 2 (TP53BP2).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Apoptosis-stimulating of p53 protein 2 (TP53BP2).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Apoptosis-stimulating of p53 protein 2 (TP53BP2).	[36]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Apoptosis-stimulating of p53 protein 2 (TP53BP2).	[37]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Apoptosis-stimulating of p53 protein 2 (TP53BP2).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Apoptosis-stimulating of p53 protein 2 (TP53BP2).	[35]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Apoptosis-stimulating of p53 protein 2 (TP53BP2).	[35]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Apoptosis-stimulating of p53 protein 2 (TP53BP2).	[38]

References

• [1] ASPP2 enhances chemotherapeutic sensitivity through the down-regulation of XIAP expression in a p53 independent manner in hepatocellular carcinoma.Biochem Biophys Res Commun. 2019 Jan 15;508(3):769-774. doi: 10.1016/j.bbrc.2018.11.181. Epub 2018 Dec 6.
• [2] ASPP2 inhibits APP-BP1-mediated NEDD8 conjugation to cullin-1 and decreases APP-BP1-induced cell proliferation and neuronal apoptosis.J Neurochem. 2003 May;85(3):801-9. doi: 10.1046/j.1471-4159.2003.01727.x.
• [3] Silencing of ASPP2 promotes the proliferation, migration and invasion of triple-negative breast cancer cells via the PI3K/AKT pathway.Int J Oncol. 2018 Jun;52(6):2001-2010. doi: 10.3892/ijo.2018.4331. Epub 2018 Mar 20.
• [4] Insertional mutagenesis identifies drivers of a novel oncogenic pathway in invasive lobular breast carcinoma.Nat Genet. 2017 Aug;49(8):1219-1230. doi: 10.1038/ng.3905. Epub 2017 Jun 26.
• [5] Expression and significance of ASPP2 in squamous carcinoma of esophagus.Kaohsiung J Med Sci. 2018 Jun;34(6):321-329. doi: 10.1016/j.kjms.2017.12.011. Epub 2018 Jan 19.
• [6] 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.
• [7] 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.
• [8] ASPP2 suppresses stem cell-like characteristics and chemoresistance by inhibiting the Src/FAK/Snail axis in hepatocellular carcinoma.Tumour Biol. 2016 Oct;37(10):13669-13677. doi: 10.1007/s13277-016-5246-0. Epub 2016 Jul 29.
• [9] Effect of miR-21 on Apoptosis in Lung Cancer Cell Through Inhibiting the PI3K/ Akt/NF-B Signaling Pathway in Vitro and in Vivo.Cell Physiol Biochem. 2018;46(3):999-1008. doi: 10.1159/000488831. Epub 2018 Apr 13.
• [10] ASPP2 suppresses squamous cell carcinoma via RelA/p65-mediated repression of p63.Proc Natl Acad Sci U S A. 2013 Oct 29;110(44):17969-74. doi: 10.1073/pnas.1309362110. Epub 2013 Oct 14.
• [11] Sensitivity of ASPP and P-gp to neoadjuvant chemotherapy combined with gene therapy in locally advanced cervical cancer.J BUON. 2019 May-Jun;24(3):967-974.
• [12] TP53BP2 decreases cell proliferation and induces autophagy in neuroblastoma cell lines.Oncol Lett. 2019 Jun;17(6):4976-4984. doi: 10.3892/ol.2019.10148. Epub 2019 Mar 15.
• [13] Abnormal expression pattern of the ASPP family of proteins in human non-small cell lung cancer and regulatory functions on apoptosis through p53 by iASPP.Oncol Rep. 2012 Jul;28(1):133-40. doi: 10.3892/or.2012.1778. Epub 2012 Apr 23.
• [14] Downregulation of ASPP2 in choriocarcinoma contributes to increased migratory potential through Src signaling pathway activation.Carcinogenesis. 2013 Sep;34(9):2170-7. doi: 10.1093/carcin/bgt161. Epub 2013 May 13.
• [15] The family of apoptosis-stimulating proteins of p53 is dysregulated in colorectal cancer patients.Oncol Lett. 2018 May;15(5):6409-6417. doi: 10.3892/ol.2018.8151. Epub 2018 Mar 1.
• [16] ASPP2 suppresses invasion and TGF-1-induced epithelial-mesenchymal transition by inhibiting Smad7 degradation mediated by E3 ubiquitin ligase ITCH in gastric cancer.Cancer Lett. 2017 Jul 10;398:52-61. doi: 10.1016/j.canlet.2017.04.002. Epub 2017 Apr 9.
• [17] Identification of gene expression models for laryngeal squamous cell carcinoma using co-expression network analysis.Medicine (Baltimore). 2018 Feb;97(7):e9738. doi: 10.1097/MD.0000000000009738.
• [18] TP53BP2 locus is associated with gastric cancer susceptibility.Int J Cancer. 2005 Dec 20;117(6):957-60. doi: 10.1002/ijc.21281.
• [19] Attenuated expression of apoptosis stimulating protein of p53-2 (ASPP2) in human acute leukemia is associated with therapy failure.PLoS One. 2013 Nov 27;8(11):e80193. doi: 10.1371/journal.pone.0080193. eCollection 2013.
• [20] Apoptosis stimulating protein of p53 (ASPP2) expression differs in diffuse large B-cell and follicular center lymphoma: correlation with clinical outcome.Leuk Lymphoma. 2002 Dec;43(12):2309-17. doi: 10.1080/1042819021000040017.
• [21] Downregulation of ASPP2 promotes gallbladder cancer metastasis and macrophage recruitment via aPKC-/GLI1 pathway.Cell Death Dis. 2018 Nov 2;9(11):1115. doi: 10.1038/s41419-018-1145-1.
• [22] Identification of TP53BP2 as a Novel Candidate Gene for Primary Open Angle Glaucoma by Whole Exome Sequencing in a Large Multiplex Family.Mol Neurobiol. 2018 Feb;55(2):1387-1395. doi: 10.1007/s12035-017-0403-z. Epub 2017 Feb 1.
• [23] A bone sialoprotein-binding protein from Staphylococcus aureus: a member of the staphylococcal Sdr family.Biochem J. 2000 Feb 1;345 Pt 3(Pt 3):611-9.
• [24] Small Interfering RNA Targeted to ASPP2 Promotes Progression of Experimental Proliferative Vitreoretinopathy.Mediators Inflamm. 2016;2016:7920631. doi: 10.1155/2016/7920631. Epub 2016 Jun 9.
• [25] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [26] 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.
• [27] 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.
• [28] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [29] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [30] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [31] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [32] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [33] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [34] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [35] 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.
• [36] Fermentation Extract of Naringenin Increases the Expression of Estrogenic Receptor and Modulates Genes Related to the p53 Signalling Pathway, miR-200c and miR-141 in Human Colon Cancer Cells Exposed to BPA. Molecules. 2022 Oct 5;27(19):6588. doi: 10.3390/molecules27196588.
• [37] Identification of genes associated with paraquat-induced toxicity in SH-SY5Y cells by PCR array focused on apoptotic pathways. J Toxicol Environ Health A. 2008;71(22):1457-67. doi: 10.1080/15287390802329364.
• [38] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
• [39] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.