Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMVUQ9W)

• DOT Name: Pleckstrin homology domain-containing family O member 1 (PLEKHO1)
• Synonyms: PH domain-containing family O member 1; C-Jun-binding protein; JBP; Casein kinase 2-interacting protein 1; CK2-interacting protein 1; CKIP-1; Osteoclast maturation-associated gene 120 protein
• Gene Name: PLEKHO1
• Related Disease:
  Adenovirus infection
  Adult lymphoma
  Advanced cancer
  Arteriosclerosis
  Arthritis
  Atherosclerosis
  Bipolar depression
  Bipolar disorder
  Congestive heart failure
  Fatty liver disease
  Glioma
  Late-onset Parkinson disease
  Lymphoma
  Lymphoma, non-Hodgkin, familial
  Myocardial infarction
  Neoplasm
  Non-hodgkin lymphoma
  Osteoporosis
  Pediatric lymphoma
  Diabetic kidney disease
  Gastric cancer
  Lung cancer
  Lung carcinoma
  Renal fibrosis
  Stomach cancer
  Rheumatoid arthritis
  Bone osteosarcoma
  Dental caries
  Osteosarcoma
• UniProt ID: PKHO1_HUMAN
• PDB ID: 3AA1
• Pfam ID: PF00169
• Sequence:
  MMKKNNSAKRGPQDGNQQPAPPEKVGWVRKFCGKGIFREIWKNRYVVLKGDQLYISEKEV
  KDEKNIQEVFDLSDYEKCEELRKSKSRSKKNHSKFTLAHSKQPGNTAPNLIFLAVSPEEK
  ESWINALNSAITRAKNRILDEVTVEEDSYLAHPTRDRAKIQHSRRPPTRGHLMAVASTST
  SDGMLTLDLIQEEDPSPEEPTSCAESFRVDLDKSVAQLAGSRRRADSDRIQPSADRASSL
  SRPWEKTDKGATYTPQAPKKLTPTEKGRCASLEEILSQRDAASARTLQLRAEEPPTPALP
  NPGQLSRIQDLVARKLEETQELLAEVQGLGDGKRKAKDPPRSPPDSESEQLLLETERLLG
  EASSNWSQAKRVLQEVRELRDLYRQMDLQTPDSHLRQTTPHSQYRKSLM
• Function: Plays a role in the regulation of the actin cytoskeleton through its interactions with actin capping protein (CP). May function to target CK2 to the plasma membrane thereby serving as an adapter to facilitate the phosphorylation of CP by protein kinase 2 (CK2). Appears to target ATM to the plasma membrane. Appears to also inhibit tumor cell growth by inhibiting AKT-mediated cell-survival. Also implicated in PI3K-regulated muscle differentiation, the regulation of AP-1 activity (plasma membrane bound AP-1 regulator that translocates to the nucleus) and the promotion of apoptosis induced by tumor necrosis factor TNF. When bound to PKB, it inhibits it probably by decreasing PKB level of phosphorylation.
• Tissue Specificity: Abundantly expressed in skeletal muscle and heart, moderately in kidney, liver, brain and placenta and sparingly in the pancreas and lung. Easily detectable in cell lines such as MOLT-4, HEK293 and Jurkat.

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenovirus infection	DISUYSBZ	Strong	Altered Expression	[1]
Adult lymphoma	DISK8IZR	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Arthritis	DIST1YEL	Strong	Genetic Variation	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Bipolar depression	DISA75FU	Strong	Biomarker	[5]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[5]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[6]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[7]
Glioma	DIS5RPEH	Strong	Biomarker	[8]
Late-onset Parkinson disease	DIS9IOUI	Strong	Altered Expression	[9]
Lymphoma	DISN6V4S	Strong	Altered Expression	[2]
Lymphoma, non-Hodgkin, familial	DISCXYIZ	Strong	Altered Expression	[2]
Myocardial infarction	DIS655KI	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Biomarker	[2]
Osteoporosis	DISF2JE0	Strong	Biomarker	[12]
Pediatric lymphoma	DIS51BK2	Strong	Altered Expression	[2]
Diabetic kidney disease	DISJMWEY	moderate	Altered Expression	[1]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[13]
Lung cancer	DISCM4YA	moderate	Altered Expression	[14]
Lung carcinoma	DISTR26C	moderate	Altered Expression	[14]
Renal fibrosis	DISMHI3I	moderate	Altered Expression	[1]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[13]
Rheumatoid arthritis	DISTSB4J	Disputed	Altered Expression	[4]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[2]
Dental caries	DISRBCMD	Limited	Altered Expression	[15]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Pleckstrin homology domain-containing family O member 1 (PLEKHO1) affects the response to substance of Fluorouracil.	[30]

16 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 Pleckstrin homology domain-containing family O member 1 (PLEKHO1).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Pleckstrin homology domain-containing family O member 1 (PLEKHO1).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Pleckstrin homology domain-containing family O member 1 (PLEKHO1).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Pleckstrin homology domain-containing family O member 1 (PLEKHO1).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Pleckstrin homology domain-containing family O member 1 (PLEKHO1).	[20]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Pleckstrin homology domain-containing family O member 1 (PLEKHO1).	[21]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Pleckstrin homology domain-containing family O member 1 (PLEKHO1).	[22]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Pleckstrin homology domain-containing family O member 1 (PLEKHO1).	[23]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Pleckstrin homology domain-containing family O member 1 (PLEKHO1).	[24]
Selenium	DM25CGV	Approved	Selenium increases the expression of Pleckstrin homology domain-containing family O member 1 (PLEKHO1).	[25]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Pleckstrin homology domain-containing family O member 1 (PLEKHO1).	[26]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Pleckstrin homology domain-containing family O member 1 (PLEKHO1).	[24]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Pleckstrin homology domain-containing family O member 1 (PLEKHO1).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Pleckstrin homology domain-containing family O member 1 (PLEKHO1).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Pleckstrin homology domain-containing family O member 1 (PLEKHO1).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Pleckstrin homology domain-containing family O member 1 (PLEKHO1).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Pleckstrin homology domain-containing family O member 1 (PLEKHO1).	[29]

References

• [1] CKIP-1 affects the polyubiquitination of Nrf2 and Keap1 via mediating Smurf1 to resist HG-induced renal fibrosis in GMCs and diabetic mice kidneys.Free Radic Biol Med. 2018 Feb 1;115:338-350. doi: 10.1016/j.freeradbiomed.2017.12.013. Epub 2017 Dec 14.
• [2] Silencing of CKIP-1 promotes tumor proliferation and cell adhesion-mediated drug resistance via regulating AKT activity in non-Hodgkin's lymphoma.Oncol Rep. 2017 Jan;37(1):622-630. doi: 10.3892/or.2016.5233. Epub 2016 Nov 8.
• [3] CKIP-1 limits foam cell formation and inhibits atherosclerosis by promoting degradation of Oct-1 by REG.Nat Commun. 2019 Jan 25;10(1):425. doi: 10.1038/s41467-018-07895-3.
• [4] Osteoblastic PLEKHO1 contributes to joint inflammation in rheumatoid arthritis.EBioMedicine. 2019 Mar;41:538-555. doi: 10.1016/j.ebiom.2019.02.009. Epub 2019 Feb 26.
• [5] Genome-wide association study identifies 30 loci associated with bipolar disorder.Nat Genet. 2019 May;51(5):793-803. doi: 10.1038/s41588-019-0397-8. Epub 2019 May 1.
• [6] Association of CKIP-1 P21A polymorphism with risk of chronic heart failure in a Chinese population.Oncotarget. 2017 May 30;8(22):36545-36552. doi: 10.18632/oncotarget.16614.
• [7] Deficiency of CKIP-1 aggravates high-fat diet-induced fatty liver in mice.Exp Cell Res. 2017 Jun 1;355(1):40-46. doi: 10.1016/j.yexcr.2017.03.033. Epub 2017 Mar 27.
• [8] Casein Kinase 2 Interacting Protein-1 Suppresses Glioma Cell Proliferation via Regulating the AKT/GSK3/-Catenin Pathway.Biomed Res Int. 2019 Jul 2;2019:5653212. doi: 10.1155/2019/5653212. eCollection 2019.
• [9] Polydatin promotes Nrf2-ARE anti-oxidative pathway through activating CKIP-1 to resist HG-induced up-regulation of FN and ICAM-1 in GMCs and diabetic mice kidneys.Free Radic Biol Med. 2017 May;106:393-405. doi: 10.1016/j.freeradbiomed.2017.03.003. Epub 2017 Mar 10.
• [10] Overexpression of CKIP-1 alleviates hypoxia-induced cardiomyocyte injury by up-regulating Nrf2 antioxidant signaling via Keap1 inhibition.Biochimie. 2019 Aug;163:163-170. doi: 10.1016/j.biochi.2019.06.008. Epub 2019 Jun 12.
• [11] PLEKHO1 knockdown inhibits RCC cell viability in vitro and in vivo, potentially by the Hippo and MAPK/JNK pathways.Int J Oncol. 2019 Jul;55(1):81-92. doi: 10.3892/ijo.2019.4819. Epub 2019 May 30.
• [12] Physiological functions of CKIP-1: From molecular mechanisms to therapy implications.Ageing Res Rev. 2019 Aug;53:100908. doi: 10.1016/j.arr.2019.05.002. Epub 2019 May 10.
• [13] The pseudogene derived long noncoding RNA DUXAP8 promotes gastric cancer cell proliferation and migration via epigenetically silencing PLEKHO1 expression.Oncotarget. 2016 Aug 5;8(32):52211-52224. doi: 10.18632/oncotarget.11075. eCollection 2017 Aug 8.
• [14] Role of the CKIP1 gene in proliferation and apoptosis of the human lung cancer cell line H1299.Genet Mol Res. 2015 Apr 27;14(2):4005-14. doi: 10.4238/2015.April.27.15.
• [15] CKIP-1 suppresses odontoblastic differentiation of dental pulp stem cells via BMP2 pathway and can interact with NRP1.Connect Tissue Res. 2019 Mar;60(2):155-164. doi: 10.1080/03008207.2018.1483355. Epub 2018 Aug 14.
• [16] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [17] 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.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [21] 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.
• [22] 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.
• [23] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [24] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [25] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [26] 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.
• [27] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [28] 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.
• [29] 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.
• [30] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.