Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHTXN1A)

• DOT Name: Calcineurin B homologous protein 1 (CHP1)
• Synonyms: Calcineurin B-like protein; Calcium-binding protein CHP; Calcium-binding protein p22; EF-hand calcium-binding domain-containing protein p22
• Gene Name: CHP1
• Related Disease:
  Primary cutaneous peripheral T-cell lymphoma not otherwise specified
  Adult T-cell leukemia/lymphoma
  Anaplastic large cell lymphoma
  Arthritis
  Cerebellar ataxia
  Chronic renal failure
  Colon carcinoma
  Cytomegalovirus infection
  End-stage renal disease
  Estrogen-receptor positive breast cancer
  Ewing sarcoma
  Focal segmental glomerulosclerosis
  Head-neck squamous cell carcinoma
  Herpes simplex infection
  Immunodeficiency
  Influenza
  Leukemia
  Lymphoma
  Medullary thyroid gland carcinoma
  Mental disorder
  Obstructive sleep apnea
  Primitive neuroectodermal tumor
  Pulmonary disease
  Schizophrenia
  Sjogren syndrome
  Spinal muscular atrophy
  T-cell leukaemia
  Tuberculosis
  Urticaria
  Kidney cancer
  Plasma cell myeloma
  Adult lymphoma
  Advanced cancer
  Autism
  Glomerulonephritis
  Hepatocellular carcinoma
  Malaria
  Mood disorder
  Myocardial infarction
  Neoplasm
  Neuroblastoma
  Osteoarthritis
  Parkinson disease
  Pediatric lymphoma
  Psychotic disorder
  Pulmonary fibrosis
  Rheumatoid arthritis
  Spastic ataxia 9, autosomal recessive
  Ulcerative colitis
• UniProt ID: CHP1_HUMAN
• PDB ID: 2E30; 7DSV; 7DSX; 7X2U
• Pfam ID: PF13499
• Sequence:
  MGSRASTLLRDEELEEIKKETGFSHSQITRLYSRFTSLDKGENGTLSREDFQRIPELAIN
  PLGDRIINAFFPEGEDQVNFRGFMRTLAHFRPIEDNEKSKDVNGPEPLNSRSNKLHFAFR
  LYDLDKDEKISRDELLQVLRMMVGVNISDEQLGSIADRTIQEADQDGDSAISFTEFVKVL
  EKVDVEQKMSIRFLH
• Function: Calcium-binding protein involved in different processes such as regulation of vesicular trafficking, plasma membrane Na(+)/H(+) exchanger and gene transcription. Involved in the constitutive exocytic membrane traffic. Mediates the association between microtubules and membrane-bound organelles of the endoplasmic reticulum and Golgi apparatus and is also required for the targeting and fusion of transcytotic vesicles (TCV) with the plasma membrane. Functions as an integral cofactor in cell pH regulation by controlling plasma membrane-type Na(+)/H(+) exchange activity. Affects the pH sensitivity of SLC9A1/NHE1 by increasing its sensitivity at acidic pH. Required for the stabilization and localization of SLC9A1/NHE1 at the plasma membrane. Inhibits serum- and GTPase-stimulated Na(+)/H(+) exchange. Plays a role as an inhibitor of ribosomal RNA transcription by repressing the nucleolar UBF1 transcriptional activity. May sequester UBF1 in the nucleoplasm and limit its translocation to the nucleolus. Associates to the ribosomal gene promoter. Acts as a negative regulator of the calcineurin/NFAT signaling pathway. Inhibits NFAT nuclear translocation and transcriptional activity by suppressing the calcium-dependent calcineurin phosphatase activity. Also negatively regulates the kinase activity of the apoptosis-induced kinase STK17B. Inhibits both STK17B auto- and substrate-phosphorylations in a calcium-dependent manner.
• Tissue Specificity: Ubiquitously expressed. Has been found in fetal eye, lung, liver, muscle, heart, kidney, thymus and spleen.
• Reactome Pathway: Hyaluronan uptake and degradation (R-HSA-2160916)

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	DIS5OHQF	Definitive	Biomarker	[1]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[2]
Anaplastic large cell lymphoma	DISP4D1R	Strong	Genetic Variation	[1]
Arthritis	DIST1YEL	Strong	Biomarker	[3]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[4]
Chronic renal failure	DISGG7K6	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[6]
Cytomegalovirus infection	DISCEMGC	Strong	Altered Expression	[7]
End-stage renal disease	DISXA7GG	Strong	Biomarker	[5]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[8]
Ewing sarcoma	DISQYLV3	Strong	Genetic Variation	[9]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Biomarker	[5]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Genetic Variation	[10]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[11]
Immunodeficiency	DIS093I0	Strong	Biomarker	[12]
Influenza	DIS3PNU3	Strong	Biomarker	[13]
Leukemia	DISNAKFL	Strong	Biomarker	[14]
Lymphoma	DISN6V4S	Strong	Biomarker	[15]
Medullary thyroid gland carcinoma	DISHBL3K	Strong	Biomarker	[16]
Mental disorder	DIS3J5R8	Strong	Biomarker	[17]
Obstructive sleep apnea	DIS0SVD1	Strong	Genetic Variation	[18]
Primitive neuroectodermal tumor	DISFHXHA	Strong	Biomarker	[19]
Pulmonary disease	DIS6060I	Strong	Altered Expression	[20]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[21]
Sjogren syndrome	DISUBX7H	Strong	Biomarker	[22]
Spinal muscular atrophy	DISTLKOB	Strong	Biomarker	[4]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[2]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[15]
Urticaria	DIS9WQAI	Strong	Altered Expression	[23]
Kidney cancer	DISBIPKM	moderate	Biomarker	[24]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[25]
Adult lymphoma	DISK8IZR	Limited	Genetic Variation	[26]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[27]
Autism	DISV4V1Z	Limited	Genetic Variation	[28]
Glomerulonephritis	DISPZIQ3	Limited	Biomarker	[29]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[30]
Malaria	DISQ9Y50	Limited	Biomarker	[31]
Mood disorder	DISLVMWO	Limited	Altered Expression	[32]
Myocardial infarction	DIS655KI	Limited	Biomarker	[29]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[10]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[33]
Osteoarthritis	DIS05URM	Limited	Biomarker	[29]
Parkinson disease	DISQVHKL	Limited	Altered Expression	[34]
Pediatric lymphoma	DIS51BK2	Limited	Genetic Variation	[26]
Psychotic disorder	DIS4UQOT	Limited	Biomarker	[32]
Pulmonary fibrosis	DISQKVLA	Limited	Biomarker	[29]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[35]
Spastic ataxia 9, autosomal recessive	DISF3V0C	Limited	Unknown	[36]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Calcineurin B homologous protein 1 (CHP1).	[38]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Calcineurin B homologous protein 1 (CHP1).	[39]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Calcineurin B homologous protein 1 (CHP1).	[40]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Calcineurin B homologous protein 1 (CHP1).	[41]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Calcineurin B homologous protein 1 (CHP1).	[42]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Calcineurin B homologous protein 1 (CHP1).	[44]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Calcineurin B homologous protein 1 (CHP1).	[45]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Calcineurin B homologous protein 1 (CHP1).	[46]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Calcineurin B homologous protein 1 (CHP1).	[48]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Calcineurin B homologous protein 1 (CHP1).	[49]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Calcineurin B homologous protein 1 (CHP1).	[50]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of Calcineurin B homologous protein 1 (CHP1).	[43]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Calcineurin B homologous protein 1 (CHP1).	[47]

References

• [1] Five-year outcomes for frontline brentuximab vedotin with CHP for CD30-expressing peripheral T-cell lymphomas.Blood. 2018 May 10;131(19):2120-2124. doi: 10.1182/blood-2017-12-821009. Epub 2018 Mar 5.
• [2] Effect of tumor promoters on human T cell leukemia/lymphoma virus (HTLV)-structural protein induction in adult T-cell leukemia cells.Cancer Lett. 1984 Sep;24(2):129-39. doi: 10.1016/0304-3835(84)90128-9.
• [3] A chromosomal Borrelia burgdorferi gene encodes a 22-kilodalton lipoprotein, P22, that is serologically recognized in Lyme disease.J Clin Microbiol. 1994 Apr;32(4):876-83. doi: 10.1128/jcm.32.4.876-883.1994.
• [4] PLS3 Overexpression Delays Ataxia in Chp1 Mutant Mice.Front Neurosci. 2019 Sep 19;13:993. doi: 10.3389/fnins.2019.00993. eCollection 2019.
• [5] Autosomal dominant progressive nephropathy with deafness: linkage to a new locus on chromosome 11q24.J Am Soc Nephrol. 2003 Jul;14(7):1794-803. doi: 10.1097/01.asn.0000071513.73427.97.
• [6] Productive in vitro infection of human umbilical vein endothelial cells and three colon carcinoma cell lines with HIV-1.Immunol Cell Biol. 1995 Apr;73(2):140-5. doi: 10.1038/icb.1995.22.
• [7] Human cytomegalovirus infection reduces surface CCR5 expression in human microglial cells, astrocytes and monocyte-derived macrophages.Microbes Infect. 2002 Nov;4(14):1401-8. doi: 10.1016/s1286-4579(02)00022-9.
• [8] Multifunctionalized biocatalytic P22 nanoreactor for combinatory treatment of ER+ breast cancer.J Nanobiotechnology. 2018 Feb 20;16(1):17. doi: 10.1186/s12951-018-0345-2.
• [9] Magnetic resonance imaging of RRx-001 pharmacodynamics in preclinical tumors.Oncotarget. 2017 Jun 12;8(60):102511-102520. doi: 10.18632/oncotarget.18455. eCollection 2017 Nov 24.
• [10] Genomic assessments of the frequent loss of heterozygosity region on 8p21.3-p22 in head and neck squamous cell carcinoma.Cancer Genet Cytogenet. 2007 Jul 15;176(2):100-6. doi: 10.1016/j.cancergencyto.2007.04.003.
• [11] Activation of Toll-like receptors inhibits herpes simplex virus-1 infection of human neuronal cells.J Neurosci Res. 2009 Oct;87(13):2916-25. doi: 10.1002/jnr.22110.
• [12] Seroprevalence of hepatitis B, hepatitis C, human immunodeficiency virus, Treponema pallidum, and co-infections among blood donors in Kyrgyzstan: a retrospective analysis (2013-2015).Infect Dis Poverty. 2017 Feb 21;6(1):45. doi: 10.1186/s40249-017-0255-9.
• [13] IL-13 acutely augments HIV-specific and recall responses from HIV-1-infected subjects in vitro by modulating monocytes.J Immunol. 2005 Oct 15;175(8):5532-40. doi: 10.4049/jimmunol.175.8.5532.
• [14] Lack of BLV and PTLV DNA sequences in the majority of patients with large granular lymphocyte leukaemia.Br J Haematol. 2000 Apr;109(1):64-70. doi: 10.1046/j.1365-2141.2000.01972.x.
• [15] HIV-associated benign lymphoepithelial cysts of the parotid glands confirmed by HIV-1 p24 antigen immunostaining.BMJ Case Rep. 2017 Sep 28;2017:bcr2017221869. doi: 10.1136/bcr-2017-221869.
• [16] Site-directed chromosome rearrangements in skin fibroblasts from persons carrying genes for hereditary neoplasms.Cancer Res. 1980 Dec;40(12):4796-803.
• [17] Detection and sequence analysis of borna disease virus p24 RNA from peripheral blood mononuclear cells of patients with mood disorders or schizophrenia and of blood donors.J Virol. 1998 Dec;72(12):10044-9. doi: 10.1128/JVI.72.12.10044-10049.1998.
• [18] Cognitive function in prepubertal children with obstructive sleep apnea: a modifying role for NADPH oxidase p22 subunit gene polymorphisms?.Antioxid Redox Signal. 2012 Jan 15;16(2):171-7. doi: 10.1089/ars.2011.4189. Epub 2011 Oct 12.
• [19] Caspase inhibition shifts neuroepithelioma cell response to okadaic acid from apoptosis to an apoptotic-like form of death.Biochem Biophys Res Commun. 2003 Apr 4;303(2):469-74. doi: 10.1016/s0006-291x(03)00358-9.
• [20] Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication in the lung.Am J Respir Crit Care Med. 1997 Mar;155(3):996-1003. doi: 10.1164/ajrccm.155.3.9117038.
• [21] Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
• [22] Retrovirus in salivary glands from patients with Sjgren's syndrome.J Clin Pathol. 1997 Mar;50(3):223-30. doi: 10.1136/jcp.50.3.223.
• [23] Molecular and pathologic insights from latent HIV-1 infection in the human brain.Neurology. 2013 Apr 9;80(15):1415-23. doi: 10.1212/WNL.0b013e31828c2e9e. Epub 2013 Mar 13.
• [24] Quantitative Contour Analysis as an Image-based Discriminator Between Benign and Malignant Renal Tumors.Urology. 2018 Apr;114:121-127. doi: 10.1016/j.urology.2017.12.018. Epub 2018 Jan 2.
• [25] Visualizing collagen proteolysis by peptide hybridization: From 3D cell culture to in vivo imaging.Biomaterials. 2018 Nov;183:67-76. doi: 10.1016/j.biomaterials.2018.08.039. Epub 2018 Aug 22.
• [26] Structural abnormalities of the X chromosome in non-Hodgkin's lymphoma.Leukemia. 1993 Jun;7(6):848-52.
• [27] Antiproliferative and Proapoptotic Effects of a Protein Component Purified from Aspongopus chinensis Dallas on Cancer Cells In Vitro and In Vivo.Evid Based Complement Alternat Med. 2019 Jan 3;2019:8934794. doi: 10.1155/2019/8934794. eCollection 2019.
• [28] A "new" chromosome marker common to the Rett syndrome and infantile autism? The frequency of fragile sites at X p22 in 81 children with infantile autism, childhood psychosis and the Rett syndrome.Brain Dev. 1985;7(3):365-7. doi: 10.1016/s0387-7604(85)80046-2.
• [29] In Situ Imaging of Tissue Remodeling with Collagen Hybridizing Peptides.ACS Nano. 2017 Oct 24;11(10):9825-9835. doi: 10.1021/acsnano.7b03150. Epub 2017 Sep 18.
• [30] Hepatitis B Virus Precore Protein p22 Inhibits Alpha Interferon Signaling by Blocking STAT Nuclear Translocation.J Virol. 2019 Jun 14;93(13):e00196-19. doi: 10.1128/JVI.00196-19. Print 2019 Jul 1.
• [31] Malaria infection induces virus expression in human immunodeficiency virus transgenic mice by CD4 T cell-dependent immune activation.J Infect Dis. 2001 Apr 15;183(8):1260-8. doi: 10.1086/319686. Epub 2001 Mar 9.
• [32] Detection of Borna disease virus p24 RNA in peripheral blood cells from Brazilian mood and psychotic disorder patients.J Affect Disord. 2006 Jan;90(1):43-7. doi: 10.1016/j.jad.2005.10.008. Epub 2005 Dec 1.
• [33] Autophagy Promotes Survival of CHP-212 Neuroblastoma Cells Treated With Casiopenas.Anticancer Res. 2019 Jul;39(7):3687-3695. doi: 10.21873/anticanres.13517.
• [34] HSP90 and Its Novel Co-Chaperones, SGT1 and CHP-1, in Brain of Patients with Parkinson's Disease and Dementia with Lewy Bodies.J Parkinsons Dis. 2019;9(1):97-107. doi: 10.3233/JPD-181443.
• [35] Cellular basis and oncogene expression of rheumatoid joint destruction.Rheumatol Int. 1989;9(3-5):105-13. doi: 10.1007/BF00271866.
• [36] Biallelic CHP1 mutation causes human autosomal recessive ataxia by impairing NHE1 function. Neurol Genet. 2018 Jan 19;4(1):e209. doi: 10.1212/NXG.0000000000000209. eCollection 2018 Feb.
• [37] Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
• [38] 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.
• [39] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [40] 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.
• [41] 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.
• [42] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [43] Ornithine decarboxylase antizyme upregulates DNA-dependent protein kinase and enhances the nonhomologous end-joining repair of DNA double-strand breaks in human oral cancer cells. Biochemistry. 2007 Aug 7;46(31):8920-32. doi: 10.1021/bi7000328. Epub 2007 Jul 14.
• [44] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [45] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [46] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [47] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [48] 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.
• [49] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [50] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.