Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ7M7G9)

• DOT Name: Gamma-secretase subunit PEN-2 (PSENEN)
• Synonyms: Presenilin enhancer protein 2
• Gene Name: PSENEN
• Related Disease:
  Acne inversa, familial, 2
  Atopic dermatitis
  Familial acne inversa
  Obesity
  Hidradenitis suppurativa
  Neuroblastoma
  Pancreatic cancer
  Dowling-Degos disease
  Familial Alzheimer disease
  Parkinson disease
• UniProt ID: PEN2_HUMAN
• PDB ID: 5A63; 5FN2; 5FN3; 5FN4; 5FN5; 6IDF; 6IYC; 6LQG; 6LR4; 7C9I; 7D8X; 7Y5T; 7Y5X; 7Y5Z
• Pfam ID: PF10251
• Sequence:
  MNLERVSNEEKLNLCRKYYLGGFAFLPFLWLVNIFWFFREAFLVPAYTEQSQIKGYVWRS
  AVGFLFWVIVLTSWITIFQIYRPRWGALGDYLSFTIPLGTP
• Function: Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (Probable). PSENEN modulates both endoproteolysis of presenilin and gamma-secretase activity.
• Tissue Specificity: Widely expressed. Expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, skeletal muscle, heart and brain.
• KEGG Pathway:
  Notch sig.ling pathway (hsa04330)
  Alzheimer disease (hsa05010)
• Reactome Pathway:
  Regulated proteolysis of p75NTR (R-HSA-193692)
  NRIF signals cell death from the nucleus (R-HSA-205043)
  Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  NOTCH2 Activation and Transmission of Signal to the Nucleus (R-HSA-2979096)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  NOTCH3 Activation and Transmission of Signal to the Nucleus (R-HSA-9013507)
  NOTCH4 Activation and Transmission of Signal to the Nucleus (R-HSA-9013700)
  Noncanonical activation of NOTCH3 (R-HSA-9017802)
  Amyloid fiber formation (R-HSA-977225)
  Nuclear signaling by ERBB4 (R-HSA-1251985)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acne inversa, familial, 2	DISAXCOV	Strong	Autosomal dominant	[1]
Atopic dermatitis	DISTCP41	Strong	Biomarker	[2]
Familial acne inversa	DIS7DVKA	Strong	Genetic Variation	[3]
Obesity	DIS47Y1K	Strong	Genetic Variation	[4]
Hidradenitis suppurativa	DIS3ZNAK	moderate	Genetic Variation	[3]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[5]
Pancreatic cancer	DISJC981	moderate	Biomarker	[6]
Dowling-Degos disease	DISGTTEP	Supportive	Autosomal dominant	[4]
Familial Alzheimer disease	DISE75U4	Limited	Genetic Variation	[7]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Gamma-secretase subunit PEN-2 (PSENEN).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Gamma-secretase subunit PEN-2 (PSENEN).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Gamma-secretase subunit PEN-2 (PSENEN).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Gamma-secretase subunit PEN-2 (PSENEN).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Gamma-secretase subunit PEN-2 (PSENEN).	[13]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Gamma-secretase subunit PEN-2 (PSENEN).	[14]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Gamma-secretase subunit PEN-2 (PSENEN).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Gamma-secretase subunit PEN-2 (PSENEN).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Gamma-secretase subunit PEN-2 (PSENEN).	[18]

1 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 Gamma-secretase subunit PEN-2 (PSENEN).	[16]

References

• [1] 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.
• [2] Identification of candidate genes in atopic dermatitis based on bioinformatic methods.Int J Dermatol. 2016 Jul;55(7):791-800. doi: 10.1111/ijd.13291. Epub 2016 Mar 9.
• [3] A phenotype combining hidradenitis suppurativa with Dowling-Degos disease caused by a founder mutation in PSENEN.Br J Dermatol. 2018 Feb;178(2):502-508. doi: 10.1111/bjd.16000. Epub 2017 Dec 18.
• [4] Mutations in -secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa. J Clin Invest. 2017 Apr 3;127(4):1485-1490. doi: 10.1172/JCI90667. Epub 2017 Mar 13.
• [5] Different kinases desensitize the human delta-opioid receptor (hDOP-R) in the neuroblastoma cell line SK-N-BE upon peptidic and alkaloid agonists.Cell Signal. 2008 Jun;20(6):1209-20. doi: 10.1016/j.cellsig.2008.02.010. Epub 2008 Feb 19.
• [6] Evaluation of the prognostic significances of -secretase genes in pancreatic cancer.Oncol Lett. 2019 May;17(5):4614-4620. doi: 10.3892/ol.2019.10113. Epub 2019 Mar 5.
• [7] Presenilin enhancer-2 gene: identification of a novel promoter mutation in a patient with early-onset familial Alzheimer's disease.Alzheimers Dement. 2011 Nov;7(6):574-8. doi: 10.1016/j.jalz.2011.02.010.
• [8] Cerebrospinal fluid A42 levels and APP processing pathway genes in Parkinson's disease.Mov Disord. 2015 Jun;30(7):936-44. doi: 10.1002/mds.26172. Epub 2015 Mar 24.
• [9] 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.
• [10] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [11] 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.
• [12] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [13] 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.
• [14] Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells. Int J Mol Sci. 2016 Dec 23;18(1):26. doi: 10.3390/ijms18010026.
• [15] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [16] 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.
• [17] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.