Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB65N2I)

DOT Name PAN2-PAN3 deadenylation complex catalytic subunit PAN2 (PAN2)
Synonyms EC 3.1.13.4; Inactive ubiquitin carboxyl-terminal hydrolase 52; PAB1P-dependent poly(A)-specific ribonuclease; Poly(A)-nuclease deadenylation complex subunit 2; PAN deadenylation complex subunit 2
Gene Name PAN2
Related Disease
Multiple congenital anomalies/dysmorphic syndrome-intellectual disability ( )
Adenocarcinoma ( )
Advanced cancer ( )
Bladder cancer ( )
Breast carcinoma ( )
Cholestasis ( )
Urinary bladder cancer ( )
Urinary bladder neoplasm ( )
Urinary tract disease ( )
UniProt ID
PAN2_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
EC Number
3.1.13.4
Pfam ID
PF20770 ; PF00929 ; PF13423
Sequence
MNFEGLDPGLAEYAPAMHSALDPVLDAHLNPSLLQNVELDPEGVALEALPVQESVHIMEG
VYSELHSVVAEVGVPVSVSHFDLHEEMLWVGSHGGHATSFFGPALERYSSFQVNGSDDIR
QIQSLENGILFLTKNNLKYMARGGLIIFDYLLDENEDMHSLLLTDSSTLLVGGLQNHIIE
IDLNTVQETQKYAVETPGVTIMRQTNRFFFCGHTSGKVSLRDLRTFKVEHEFDAFSGSLS
DFDVHGNLLAACGFSSRLTGLACDRFLKVYDLRMMRAITPLQVHVDPAFLRFIPTYTSRL
AIISQSGQCQFCEPTGLANPADIFHVNPVGPLLMTFDVSASKQALAFGDSEGCVHLWTDS
PEPSFNPYSRETEFALPCLVDSLPPLDWSQDLLPLSLIPVPLTTDTLLSDWPAANSAPAP
RRAPPVDAEILRTMKKVGFIGYAPNPRTRLRNQIPYRLKESDSEFDSFSQVTESPVGREE
EPHLHMVSKKYRKVTIKYSKLGLEDFDFKHYNKTLFAGLEPHIPNAYCNCMIQVLYFLEP
VRCLIQNHLCQKEFCLACELGFLFHMLDLSRGDPCQGNNFLRAFRTIPEASALGLILADS
DEASGKGNLARLIQRWNRFILTQLHQDMQELEIPQAYRGAGGSSFCSSGDSVIGQLFSCE
MENCSLCRCGSETVRASSTLLFTLSYPDGSKSDKTGKNYDFAQVLKRSICLDQNTQAWCD
TCEKYQPTIQTRNIRHLPDILVINCEVNSSKEADFWRMQAEVAFKMAVKKHGGEISKNKE
FALADWKELGSPEGVLVCPSIEELKNVWLPFSIRMKMTKNKGLDVCNWTDGDEMQWGPAR
AEEEHGVYVYDLMATVVHILDSRTGGSLVAHIKVGETYHQRKEGVTHQQWYLFNDFLIEP
IDKHEAVQFDMNWKVPAILYYVKRNLNSRYNLNIKNPIEASVLLAEASLARKQRKTHTTF
IPLMLNEMPQIGDLVGLDAEFVTLNEEEAELRSDGTKSTIKPSQMSVARITCVRGQGPNE
GIPFIDDYISTQEQVVDYLTQYSGIKPGDLDAKISSKHLTTLKSTYLKLRFLIDIGVKFV
GHGLQKDFRVINLMVPKDQVLDTVYLFHMPRKRMISLRFLAWYFLDLKIQGETHDSIEDA
RTALQLYRKYLELSKNGTEPESFHKVLKGLYEKGRKMDWKVPEPEGQTSPKNAAVFSSVL
AL
Function
Catalytic subunit of the poly(A)-nuclease (PAN) deadenylation complex, one of two cytoplasmic mRNA deadenylases involved in general and miRNA-mediated mRNA turnover. PAN specifically shortens poly(A) tails of RNA and the activity is stimulated by poly(A)-binding protein (PABP). PAN deadenylation is followed by rapid degradation of the shortened mRNA tails by the CCR4-NOT complex. Deadenylated mRNAs are then degraded by two alternative mechanisms, namely exosome-mediated 3'-5' exonucleolytic degradation, or deadenylation-dependent mRNA decaping and subsequent 5'-3' exonucleolytic degradation by XRN1. Also acts as an important regulator of the HIF1A-mediated hypoxic response. Required for HIF1A mRNA stability independent of poly(A) tail length regulation.
KEGG Pathway
R. degradation (hsa03018 )
Reactome Pathway
Deadenylation of mRNA (R-HSA-429947 )

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Multiple congenital anomalies/dysmorphic syndrome-intellectual disability DISDOXWZ Definitive Autosomal recessive [1]
Adenocarcinoma DIS3IHTY Strong Altered Expression [2]
Advanced cancer DISAT1Z9 Strong Biomarker [3]
Bladder cancer DISUHNM0 Strong Altered Expression [4]
Breast carcinoma DIS2UE88 Strong Altered Expression [5]
Cholestasis DISDJJWE Strong Biomarker [6]
Urinary bladder cancer DISDV4T7 Strong Altered Expression [4]
Urinary bladder neoplasm DIS7HACE Strong Altered Expression [4]
Urinary tract disease DIS0HU8N Strong Altered Expression [4]
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⏷ Show the Full List of 9 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
14 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 PAN2-PAN3 deadenylation complex catalytic subunit PAN2 (PAN2). [7]
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of PAN2-PAN3 deadenylation complex catalytic subunit PAN2 (PAN2). [8]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of PAN2-PAN3 deadenylation complex catalytic subunit PAN2 (PAN2). [9]
Doxorubicin DMVP5YE Approved Doxorubicin increases the expression of PAN2-PAN3 deadenylation complex catalytic subunit PAN2 (PAN2). [10]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate decreases the expression of PAN2-PAN3 deadenylation complex catalytic subunit PAN2 (PAN2). [11]
Estradiol DMUNTE3 Approved Estradiol decreases the expression of PAN2-PAN3 deadenylation complex catalytic subunit PAN2 (PAN2). [12]
Quercetin DM3NC4M Approved Quercetin increases the expression of PAN2-PAN3 deadenylation complex catalytic subunit PAN2 (PAN2). [13]
Temozolomide DMKECZD Approved Temozolomide increases the expression of PAN2-PAN3 deadenylation complex catalytic subunit PAN2 (PAN2). [14]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide decreases the expression of PAN2-PAN3 deadenylation complex catalytic subunit PAN2 (PAN2). [15]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide affects the expression of PAN2-PAN3 deadenylation complex catalytic subunit PAN2 (PAN2). [16]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of PAN2-PAN3 deadenylation complex catalytic subunit PAN2 (PAN2). [17]
THAPSIGARGIN DMDMQIE Preclinical THAPSIGARGIN increases the expression of PAN2-PAN3 deadenylation complex catalytic subunit PAN2 (PAN2). [21]
Formaldehyde DM7Q6M0 Investigative Formaldehyde increases the expression of PAN2-PAN3 deadenylation complex catalytic subunit PAN2 (PAN2). [22]
Coumestrol DM40TBU Investigative Coumestrol increases the expression of PAN2-PAN3 deadenylation complex catalytic subunit PAN2 (PAN2). [23]
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⏷ Show the Full List of 14 Drug(s)
3 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Fulvestrant DM0YZC6 Approved Fulvestrant increases the methylation of PAN2-PAN3 deadenylation complex catalytic subunit PAN2 (PAN2). [18]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the methylation of PAN2-PAN3 deadenylation complex catalytic subunit PAN2 (PAN2). [19]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 decreases the phosphorylation of PAN2-PAN3 deadenylation complex catalytic subunit PAN2 (PAN2). [20]
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References

1 Expanding the phenome and variome of skeletal dysplasia. Genet Med. 2018 Dec;20(12):1609-1616. doi: 10.1038/gim.2018.50. Epub 2018 Apr 5.
2 Biologic instability of pancreatic cancer xenografts in the nude mouse.Carcinogenesis. 2000 Jun;21(6):1121-7.
3 Lewis and secretor gene dosages affect CA19-9 and DU-PAN-2 serum levels in normal individuals and colorectal cancer patients.Cancer Res. 1998 Feb 1;58(3):512-8.
4 Evaluation of urinary CA19-9 levels in bladder cancer patients classified according to the combinations of Lewis and Secretor blood group genotypes.Int J Urol. 2007 Sep;14(9):795-9. doi: 10.1111/j.1442-2042.2007.01840.x.
5 USP52 acts as a deubiquitinase and promotes histone chaperone ASF1A stabilization.Nat Commun. 2018 Mar 29;9(1):1285. doi: 10.1038/s41467-018-03588-z.
6 Classification of Cholestatic and Necrotic Hepatotoxicants Using Transcriptomics on Human Precision-Cut Liver Slices.Chem Res Toxicol. 2016 Mar 21;29(3):342-51. doi: 10.1021/acs.chemrestox.5b00491. Epub 2016 Mar 9.
7 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
8 Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
9 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.
10 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.
11 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
12 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
13 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.
14 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.
15 Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
16 Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
17 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.
18 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.
19 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.
20 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.
21 Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
22 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
23 Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.