Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0AQD93)

• DOT Name: Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC)
• Synonyms: EC 3.1.3.16; CAM-PRP catalytic subunit; Calcineurin, testis-specific catalytic subunit; Calmodulin-dependent calcineurin A subunit gamma isoform
• Gene Name: PPP3CC
• Related Disease:
  Bipolar disorder
  Bladder cancer
  Depression
  Prostate neoplasm
  Psychotic disorder
  Urinary bladder cancer
  Urinary bladder neoplasm
  Castration-resistant prostate carcinoma
  Schizophrenia
• UniProt ID: PP2BC_HUMAN
• PDB ID: 7U0T
• EC Number: 3.1.3.16
• Pfam ID: PF00149
• Sequence:
  MSGRRFHLSTTDRVIKAVPFPPTQRLTFKEVFENGKPKVDVLKNHLVKEGRLEEEVALKI
  INDGAAILRQEKTMIEVDAPITVCGDIHGQFFDLMKLFEVGGSPSNTRYLFLGDYVDRGY
  FSIECVLYLWSLKINHPKTLFLLRGNHECRHLTDYFTFKQECRIKYSEQVYDACMETFDC
  LPLAALLNQQFLCVHGGMSPEITSLDDIRKLDRFTEPPAFGPVCDLLWSDPSEDYGNEKT
  LEHYTHNTVRGCSYFYSYPAVCEFLQNNNLLSIIRAHEAQDAGYRMYRKSQATGFPSLIT
  IFSAPNYLDVYNNKAAVLKYENNVMNIRQFNCSPHPYWLPNFMDVFTWSLPFVGEKVTEM
  LVNVLNICSDDELISDDEAEGSTTVRKEIIRNKIRAIGKMARVFSILRQESESVLTLKGL
  TPTGTLPLGVLSGGKQTIETATVEAVEAREAIRGFSLQHKIRSFEEARGLDRINERMPPR
  KDSIHAGGPMKSVTSAHSHAAHRSDQGKKAHS
• Function: Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals. Dephosphorylates and activates transcription factor NFATC1. Dephosphorylates and inactivates transcription factor ELK1. Dephosphorylates DARPP32.
• Tissue Specificity: Testis.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  Oocyte meiosis (hsa04114)
  Cellular senescence (hsa04218)
  Wnt sig.ling pathway (hsa04310)
  Axon guidance (hsa04360)
  VEGF sig.ling pathway (hsa04370)
  Osteoclast differentiation (hsa04380)
  C-type lectin receptor sig.ling pathway (hsa04625)
  .tural killer cell mediated cytotoxicity (hsa04650)
  Th1 and Th2 cell differentiation (hsa04658)
  Th17 cell differentiation (hsa04659)
  T cell receptor sig.ling pathway (hsa04660)
  B cell receptor sig.ling pathway (hsa04662)
  Long-term potentiation (hsa04720)
  Glutamatergic sy.pse (hsa04724)
  Dopaminergic sy.pse (hsa04728)
  Oxytocin sig.ling pathway (hsa04921)
  Glucagon sig.ling pathway (hsa04922)
  Renin secretion (hsa04924)
  Alzheimer disease (hsa05010)
  Amyotrophic lateral sclerosis (hsa05014)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Amphetamine addiction (hsa05031)
  Tuberculosis (hsa05152)
  Human cytomegalovirus infection (hsa05163)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Human immunodeficiency virus 1 infection (hsa05170)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  DARPP-32 events (R-HSA-180024)
  Activation of BAD and translocation to mitochondria (R-HSA-111447)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bipolar disorder	DISAM7J2	Strong	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Genetic Variation	[2]
Depression	DIS3XJ69	Strong	Biomarker	[1]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[3]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[4]
Urinary bladder cancer	DISDV4T7	Strong	Genetic Variation	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Genetic Variation	[2]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Biomarker	[5]
Schizophrenia	DISSRV2N	No Known	Unknown	[6]

18 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 Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC).	[14]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC).	[15]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC).	[12]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC).	[17]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC).	[18]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC).	[22]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC).	[24]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC).	[25]

2 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 increases the methylation of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PPP3CC).	[23]

References

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• [5] A Constitutive Intrinsic Inflammatory Signaling Circuit Composed of miR-196b, Meis2, PPP3CC, and p65 Drives Prostate Cancer Castration Resistance.Mol Cell. 2017 Jan 5;65(1):154-167. doi: 10.1016/j.molcel.2016.11.034. Epub 2016 Dec 29.
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• [14] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
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• [16] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [19] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [20] 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.
• [21] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] 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.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [25] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.