Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJBN41W)

• DOT Name: E3 ubiquitin-protein ligase parkin (PRKN)
• Synonyms: Parkin; EC 2.3.2.31; Parkin RBR E3 ubiquitin-protein ligase; Parkinson juvenile disease protein 2; Parkinson disease protein 2
• Gene Name: PRKN
• Related Disease:
  Autosomal recessive juvenile Parkinson disease 2
  Clear cell renal carcinoma
  Intervertebral disc degeneration
  Lafora disease
  Parkinson disease
  Acute myelogenous leukaemia
  Adult lymphoma
  Alzheimer disease
  Angelman syndrome
  Autism
  Autoimmune disease
  Breast neoplasm
  Colonic neoplasm
  Colorectal carcinoma
  Dystonia
  Epithelial ovarian cancer
  Fanconi anemia complementation group A
  Fanconi's anemia
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Herpes simplex infection
  Juvenile-onset Parkinson disease
  Lung cancer
  Lung neoplasm
  Lymphoma
  Neoplasm
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Pancreatic cancer
  Pediatric lymphoma
  Rheumatoid arthritis
  Subarachnoid hemorrhage
  Vesicoureteral reflux
  Von hippel-lindau disease
  Idiopathic parkinson disease
  Lung carcinoma
  Neurodegenerative disease
  Neurodevelopmental disorder
  Ovarian cancer
  Young-onset Parkinson disease
  Adult glioblastoma
  Colon cancer
  Leprosy
  Ovarian neoplasm
  Restless legs syndrome
  Schizophrenia
• UniProt ID: PRKN_HUMAN
• PDB ID: 1IYF; 2JMO; 4BM9; 4I1F; 4I1H; 5C1Z; 5C23; 5C9V; 5N2W; 5N38; 5TR5; 6GLC; 6HUE; 6N13
• EC Number: 2.3.2.31
• Pfam ID: PF00240 ; PF17976 ; PF17978
• Sequence:
  MIVFVRFNSSHGFPVEVDSDTSIFQLKEVVAKRQGVPADQLRVIFAGKELRNDWTVQNCD
  LDQQSIVHIVQRPWRKGQEMNATGGDDPRNAAGGCEREPQSLTRVDLSSSVLPGDSVGLA
  VILHTDSRKDSPPAGSPAGRSIYNSFYVYCKGPCQRVQPGKLRVQCSTCRQATLTLTQGP
  SCWDDVLIPNRMSGECQSPHCPGTSAEFFFKCGAHPTSDKETSVALHLIATNSRNITCIT
  CTDVRSPVLVFQCNSRHVICLDCFHLYCVTRLNDRQFVHDPQLGYSLPCVAGCPNSLIKE
  LHHFRILGEEQYNRYQQYGAEECVLQMGGVLCPRPGCGAGLLPEPDQRKVTCEGGNGLGC
  GFAFCRECKEAYHEGECSAVFEASGTTTQAYRVDERAAEQARWEAASKETIKKTTKPCPR
  CHVPVEKNGGCMHMKCPQPQCRLEWCWNCGCEWNRVCMGDHWFDV
• Function: Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. Substrates include SYT11 and VDAC1. Other substrates are BCL2, CCNE1, GPR37, RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPTIN5, TOMM20, USP30, ZNF746, MIRO1 and AIMP2. Mediates monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context. Participates in the removal and/or detoxification of abnormally folded or damaged protein by mediating 'Lys-63'-linked polyubiquitination of misfolded proteins such as PARK7: 'Lys-63'-linked polyubiquitinated misfolded proteins are then recognized by HDAC6, leading to their recruitment to aggresomes, followed by degradation. Mediates 'Lys-63'-linked polyubiquitination of a 22 kDa O-linked glycosylated isoform of SNCAIP, possibly playing a role in Lewy-body formation. Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy. Protects against mitochondrial dysfunction during cellular stress, by acting downstream of PINK1 to coordinate mitochondrial quality control mechanisms that remove and replace dysfunctional mitochondrial components. Depending on the severity of mitochondrial damage and/or dysfunction, activity ranges from preventing apoptosis and stimulating mitochondrial biogenesis to regulating mitochondrial dynamics and eliminating severely damaged mitochondria via mitophagy. Activation and recruitment onto the outer membrane of damaged/dysfunctional mitochondria (OMM) requires PINK1-mediated phosphorylation of both PRKN and ubiquitin. After mitochondrial damage, functions with PINK1 to mediate the decision between mitophagy or preventing apoptosis by inducing either the poly- or monoubiquitination of VDAC1, respectively; polyubiquitination of VDAC1 promotes mitophagy, while monoubiquitination of VDAC1 decreases mitochondrial calcium influx which ultimately inhibits apoptosis. When cellular stress results in irreversible mitochondrial damage, promotes the autophagic degradation of dysfunctional depolarized mitochondria (mitophagy) by promoting the ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1, MFN1 and USP30. Preferentially assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains, leading to mitophagy. The PINK1-PRKN pathway also promotes fission of damaged mitochondria by PINK1-mediated phosphorylation which promotes the PRKN-dependent degradation of mitochondrial proteins involved in fission such as MFN2. This prevents the refusion of unhealthy mitochondria with the mitochondrial network or initiates mitochondrial fragmentation facilitating their later engulfment by autophagosomes. Regulates motility of damaged mitochondria via the ubiquitination and subsequent degradation of MIRO1 and MIRO2; in motor neurons, this likely inhibits mitochondrial intracellular anterograde transport along the axons which probably increases the chance of the mitochondria undergoing mitophagy in the soma. Involved in mitochondrial biogenesis via the 'Lys-48'-linked polyubiquitination of transcriptional repressor ZNF746/PARIS which leads to its subsequent proteasomal degradation and allows activation of the transcription factor PPARGC1A. Limits the production of reactive oxygen species (ROS). Regulates cyclin-E during neuronal apoptosis. In collaboration with CHPF isoform 2, may enhance cell viability and protect cells from oxidative stress. Independently of its ubiquitin ligase activity, protects from apoptosis by the transcriptional repression of p53/TP53. May protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, and kainate-induced excitotoxicity. May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. May represent a tumor suppressor gene.
• Tissue Specificity: Highly expressed in the brain including the substantia nigra . Expressed in heart, testis and skeletal muscle . Expression is down-regulated or absent in tumor biopsies, and absent in the brain of PARK2 patients . Overexpression protects dopamine neurons from kainate-mediated apoptosis . Found in serum (at protein level) .
• KEGG Pathway:
  Ubiquitin mediated proteolysis (hsa04120)
  Mitophagy - animal (hsa04137)
  Protein processing in endoplasmic reticulum (hsa04141)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  Regulation of necroptotic cell death (R-HSA-5675482)
  Josephin domain DUBs (R-HSA-5689877)
  Aggrephagy (R-HSA-9646399)
  Amyloid fiber formation (R-HSA-977225)
  Antigen processing (R-HSA-983168)
  PINK1-PRKN Mediated Mitophagy (R-HSA-5205685)

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive juvenile Parkinson disease 2	DISNSTD1	Definitive	Autosomal recessive	[1]
Clear cell renal carcinoma	DISBXRFJ	Definitive	Altered Expression	[2]
Intervertebral disc degeneration	DISG3AIM	Definitive	Genetic Variation	[3]
Lafora disease	DIS83JHH	Definitive	Biomarker	[4]
Parkinson disease	DISQVHKL	Definitive	Autosomal recessive	[5]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[6]
Adult lymphoma	DISK8IZR	Strong	Altered Expression	[7]
Alzheimer disease	DISF8S70	Strong	Biomarker	[8]
Angelman syndrome	DIS4QVXO	Strong	Genetic Variation	[9]
Autism	DISV4V1Z	Strong	Genetic Variation	[10]
Autoimmune disease	DISORMTM	Strong	Altered Expression	[11]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[12]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[13]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[14]
Dystonia	DISJLFGW	Strong	Genetic Variation	[15]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[16]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[17]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[17]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[18]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[19]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[20]
Juvenile-onset Parkinson disease	DISNT5BI	Strong	Genetic Variation	[21]
Lung cancer	DISCM4YA	Strong	Biomarker	[22]
Lung neoplasm	DISVARNB	Strong	Biomarker	[23]
Lymphoma	DISN6V4S	Strong	Altered Expression	[7]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[22]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[24]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[25]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[26]
Pediatric lymphoma	DIS51BK2	Strong	Altered Expression	[7]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[27]
Subarachnoid hemorrhage	DISI7I8Y	Strong	Therapeutic	[28]
Vesicoureteral reflux	DISUL6SA	Strong	Genetic Variation	[29]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Biomarker	[30]
Idiopathic parkinson disease	DIS18PD0	moderate	Biomarker	[31]
Lung carcinoma	DISTR26C	moderate	Biomarker	[22]
Neurodegenerative disease	DISM20FF	moderate	Biomarker	[32]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[33]
Ovarian cancer	DISZJHAP	moderate	Biomarker	[16]
Young-onset Parkinson disease	DIS05LFS	Supportive	Autosomal recessive	[34]
Adult glioblastoma	DISVP4LU	Disputed	Altered Expression	[18]
Colon cancer	DISVC52G	Limited	Genetic Variation	[35]
Leprosy	DISAA4UI	Limited	Genetic Variation	[36]
Ovarian neoplasm	DISEAFTY	Limited	Biomarker	[16]
Restless legs syndrome	DISNWY00	Limited	Biomarker	[37]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Levodopa	DMN3E57	Approved	E3 ubiquitin-protein ligase parkin (PRKN) increases the Dyskinesias and movement disorders NEC ADR of Levodopa.	[59]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of E3 ubiquitin-protein ligase parkin (PRKN).	[39]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of E3 ubiquitin-protein ligase parkin (PRKN).	[41]
Sorafenib	DMS8IFC	Approved	Sorafenib increases the ubiquitination of E3 ubiquitin-protein ligase parkin (PRKN).	[45]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase parkin (PRKN).	[40]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of E3 ubiquitin-protein ligase parkin (PRKN).	[42]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of E3 ubiquitin-protein ligase parkin (PRKN).	[43]
Methamphetamine	DMPM4SK	Approved	Methamphetamine decreases the expression of E3 ubiquitin-protein ligase parkin (PRKN).	[44]
Dopamine	DMPGUCF	Approved	Dopamine increases the expression of E3 ubiquitin-protein ligase parkin (PRKN).	[46]
Tubocurarine	DMBZIVP	Approved	Tubocurarine decreases the expression of E3 ubiquitin-protein ligase parkin (PRKN).	[43]
Emtricitabine	DMBMUWZ	Approved	Emtricitabine decreases the expression of E3 ubiquitin-protein ligase parkin (PRKN).	[48]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of E3 ubiquitin-protein ligase parkin (PRKN).	[49]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of E3 ubiquitin-protein ligase parkin (PRKN).	[50]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase parkin (PRKN).	[51]
MG-132	DMKA2YS	Preclinical	MG-132 decreases the expression of E3 ubiquitin-protein ligase parkin (PRKN).	[52]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of E3 ubiquitin-protein ligase parkin (PRKN).	[42]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of E3 ubiquitin-protein ligase parkin (PRKN).	[53]
Manganese	DMKT129	Investigative	Manganese decreases the expression of E3 ubiquitin-protein ligase parkin (PRKN).	[54]
Benzoquinone	DMNBA0G	Investigative	Benzoquinone increases the expression of E3 ubiquitin-protein ligase parkin (PRKN).	[57]
[3H]CP55940	DMU7FC5	Investigative	[3H]CP55940 increases the expression of E3 ubiquitin-protein ligase parkin (PRKN).	[58]

3 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Trifluoperazine	DMKBYWI	Approved	Trifluoperazine affects the localization of E3 ubiquitin-protein ligase parkin (PRKN).	[47]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos affects the localization of E3 ubiquitin-protein ligase parkin (PRKN).	[55]
Lead acetate	DML0GZ2	Investigative	Lead acetate affects the localization of E3 ubiquitin-protein ligase parkin (PRKN).	[56]

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] HIF2-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma.Mol Cancer Ther. 2018 Jan;17(1):140-149. doi: 10.1158/1535-7163.MCT-17-0471. Epub 2017 Oct 27.
• [3] Novel genetic variants associated with lumbar disc degeneration in northern Europeans: a meta-analysis of 4600 subjects.Ann Rheum Dis. 2013 Jul;72(7):1141-8. doi: 10.1136/annrheumdis-2012-201551. Epub 2012 Sep 19.
• [4] Regulation of the autophagic PI3KC3 complex by laforin/malin E3-ubiquitin ligase, two proteins involved in Lafora disease.Biochim Biophys Acta Mol Cell Res. 2020 Feb;1867(2):118613. doi: 10.1016/j.bbamcr.2019.118613. Epub 2019 Nov 21.
• [5] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [6] Loss of FBXO9 Enhances Proteasome Activity and Promotes Aggressiveness in Acute Myeloid Leukemia.Cancers (Basel). 2019 Nov 3;11(11):1717. doi: 10.3390/cancers11111717.
• [7] Activation of MET signaling by HDAC6 offers a rationale for a novel ricolinostat and crizotinib combinatorial therapeutic strategy in diffuse large B-cell lymphoma.J Pathol. 2018 Oct;246(2):141-153. doi: 10.1002/path.5108. Epub 2018 Aug 20.
• [8] Parkin Overexpression Ameliorates PrP106-126-Induced Neurotoxicity via Enhanced Autophagy in N2a Cells.Cell Mol Neurobiol. 2017 May;37(4):717-728. doi: 10.1007/s10571-016-0407-7. Epub 2016 Jul 18.
• [9] A bipartite boundary element restricts UBE3A imprinting to mature neurons.Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2181-2186. doi: 10.1073/pnas.1815279116. Epub 2019 Jan 23.
• [10] Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3.Mol Psychiatry. 2021 May;26(5):1491-1504. doi: 10.1038/s41380-019-0498-x. Epub 2019 Aug 27.
• [11] The E3 ubiquitin ligase Itch restricts antigen-driven B cell responses.J Exp Med. 2019 Sep 2;216(9):2170-2183. doi: 10.1084/jem.20181953. Epub 2019 Jul 16.
• [12] Deubiquitinase ubiquitin-specific protease 9X regulates the stability and function of E3 ubiquitin ligase ring finger protein 115 in breast cancer cells.Cancer Sci. 2019 Apr;110(4):1268-1278. doi: 10.1111/cas.13953. Epub 2019 Feb 21.
• [13] Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies.Nat Genet. 2010 Jan;42(1):77-82. doi: 10.1038/ng.491. Epub 2009 Nov 29.
• [14] TRAF6 inhibits colorectal cancer metastasis through regulating selective autophagic CTNNB1/-catenin degradation and is targeted for GSK3B/GSK3-mediated phosphorylation and degradation.Autophagy. 2019 Sep;15(9):1506-1522. doi: 10.1080/15548627.2019.1586250. Epub 2019 Mar 4.
• [15] Clinical and neuroimaging phenotypes of genetic parkinsonism from infancy to adolescence.Brain. 2020 Mar 1;143(3):751-770. doi: 10.1093/brain/awz345.
• [16] Cul4 E3 ubiquitin ligase regulates ovarian cancer drug resistance by targeting the antiapoptotic protein BIRC3.Cell Death Dis. 2019 Feb 4;10(2):104. doi: 10.1038/s41419-018-1200-y.
• [17] High expression of UBE2T predicts poor prognosis and survival in multiple myeloma.Cancer Gene Ther. 2019 Nov;26(11-12):347-355. doi: 10.1038/s41417-018-0070-x. Epub 2019 Jan 9.
• [18] TRIM8-driven transcriptomic profile of neural stem cells identified glioma-related nodal genes and pathways.Biochim Biophys Acta Gen Subj. 2019 Feb;1863(2):491-501. doi: 10.1016/j.bbagen.2018.12.001. Epub 2018 Dec 5.
• [19] Parkin facilitates proteasome inhibitor-induced apoptosis via suppression of NF-B activity in hepatocellular carcinoma.Cell Death Dis. 2019 Sep 26;10(10):719. doi: 10.1038/s41419-019-1881-x.
• [20] Characterization of Elements Regulating the Nuclear-to-Cytoplasmic Translocation of ICP0 in Late Herpes Simplex Virus 1 Infection.J Virol. 2018 Jan 2;92(2):e01673-17. doi: 10.1128/JVI.01673-17. Print 2018 Jan 15.
• [21] Identification of mutations in the PARK2 gene in Serbian patients with Parkinson's disease.J Neurol Sci. 2018 Oct 15;393:27-30. doi: 10.1016/j.jns.2018.07.020. Epub 2018 Jul 24.
• [22] Somatic and germline mutations in the tumor suppressor gene PARK2 impair PINK1/Parkin-mediated mitophagy in lung cancer cells.Acta Pharmacol Sin. 2020 Jan;41(1):93-100. doi: 10.1038/s41401-019-0260-6. Epub 2019 Jul 8.
• [23] A recurrent mutation in PARK2 is associated with familial lung cancer.Am J Hum Genet. 2015 Feb 5;96(2):301-8. doi: 10.1016/j.ajhg.2014.12.016. Epub 2015 Jan 29.
• [24] The E3 ubiquitin ligase parkin is dispensable for metabolic homeostasis in murine pancreatic cells and adipocytes.J Biol Chem. 2019 May 3;294(18):7296-7307. doi: 10.1074/jbc.RA118.006763. Epub 2019 Mar 15.
• [25] LncRNA DUXAP9-206 directly binds with Cbl-b to augment EGFR signaling and promotes non-small cell lung cancer progression.J Cell Mol Med. 2019 Mar;23(3):1852-1864. doi: 10.1111/jcmm.14085. Epub 2018 Dec 4.
• [26] PINK1 and PARK2 Suppress Pancreatic Tumorigenesis through Control of Mitochondrial Iron-Mediated Immunometabolism.Dev Cell. 2018 Aug 20;46(4):441-455.e8. doi: 10.1016/j.devcel.2018.07.012. Epub 2018 Aug 9.
• [27] Upregulation of HRD1 promotes cell migration and invasion in colon cancer.Mol Cell Biochem. 2019 Apr;454(1-2):1-9. doi: 10.1007/s11010-018-3447-0. Epub 2018 Oct 10.
• [28] Melatonin-mediated mitophagy protects against early brain injury after subarachnoid hemorrhage through inhibition of NLRP3 inflammasome activation.Sci Rep. 2017 May 25;7(1):2417. doi: 10.1038/s41598-017-02679-z.
• [29] Genome-wide linkage and association study implicates the 10q26 region as a major genetic contributor to primary nonsyndromic vesicoureteric reflux.Sci Rep. 2017 Nov 6;7(1):14595. doi: 10.1038/s41598-017-15062-9.
• [30] Role of the VHL (von Hippel-Lindau) gene in renal cancer: a multifunctional tumour suppressor.Biochem Soc Trans. 2008 Jun;36(Pt 3):472-8. doi: 10.1042/BST0360472.
• [31] Effects of cinnarizine, a calcium antagonist that produces human parkinsonism, in parkin knock out mice.Neuropharmacology. 2005 Aug;49(2):208-19. doi: 10.1016/j.neuropharm.2005.03.003.
• [32] Drosophila overexpressing parkin R275W mutant exhibits dopaminergic neuron degeneration and mitochondrial abnormalities.J Neurosci. 2007 Aug 8;27(32):8563-70. doi: 10.1523/JNEUROSCI.0218-07.2007.
• [33] Imprinting effects of UBE3A loss on synaptic gene networks and Wnt signaling pathways.Hum Mol Genet. 2019 Nov 15;28(22):3842-3852. doi: 10.1093/hmg/ddz221.
• [34] Role of mendelian genes in "sporadic" Parkinson's disease. Parkinsonism Relat Disord. 2012 Jan;18 Suppl 1:S66-70. doi: 10.1016/S1353-8020(11)70022-0.
• [35] A colon cancer-derived mutant of Krppel-like factor 5 (KLF5) is resistant to degradation by glycogen synthase kinase 3 (GSK3) and the E3 ubiquitin ligase F-box and WD repeat domain-containing 7 (FBW7).J Biol Chem. 2014 Feb 28;289(9):5997-6005. doi: 10.1074/jbc.M113.508549. Epub 2014 Jan 7.
• [36] Post-translational modification of Parkin and its research progress in cancer.Cancer Commun (Lond). 2019 Nov 21;39(1):77. doi: 10.1186/s40880-019-0421-5.
• [37] Parkin gene modifies the effect of RLS4 on the age at onset of restless legs syndrome (RLS).Am J Med Genet B Neuropsychiatr Genet. 2010 Jan 5;153B(1):350-5. doi: 10.1002/ajmg.b.30988.
• [38] Genome-wide association study of paliperidone efficacy.Pharmacogenet Genomics. 2017 Jan;27(1):7-18. doi: 10.1097/FPC.0000000000000250.
• [39] 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.
• [40] 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.
• [41] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [42] Silibinin inhibits ethanol- or acetaldehyde-induced ferroptosis in liver cell lines. Toxicol In Vitro. 2022 Aug;82:105388. doi: 10.1016/j.tiv.2022.105388. Epub 2022 May 18.
• [43] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [44] Involvement of C/EBP-related signaling pathway in methamphetamine-induced neuronal autophagy and apoptosis. Toxicol Lett. 2019 Sep 15;312:11-21. doi: 10.1016/j.toxlet.2019.05.003. Epub 2019 May 3.
• [45] Sorafenib targets the mitochondrial electron transport chain complexes and ATP synthase to activate the PINK1-Parkin pathway and modulate cellular drug response. J Biol Chem. 2017 Sep 8;292(36):15105-15120. doi: 10.1074/jbc.M117.783175. Epub 2017 Jul 3.
• [46] Induction of parkin expression in the presence of oxidative stress. Eur J Neurosci. 2006 Sep;24(5):1366-72. doi: 10.1111/j.1460-9568.2006.04998.x.
• [47] Rescue of Pink1 Deficiency by Stress-Dependent Activation of Autophagy. Cell Chem Biol. 2017 Apr 20;24(4):471-480.e4. doi: 10.1016/j.chembiol.2017.03.005. Epub 2017 Mar 30.
• [48] Chronic Nucleoside Reverse Transcriptase Inhibitors Disrupt Mitochondrial Homeostasis and Promote Premature Endothelial Senescence. Toxicol Sci. 2019 Dec 1;172(2):445-456. doi: 10.1093/toxsci/kfz203.
• [49] Gene expression and cytosine DNA methylation alterations in induced pluripotent stem-cell-derived human hepatocytes treated with low doses of chemical carcinogens. Arch Toxicol. 2019 Nov;93(11):3335-3344. doi: 10.1007/s00204-019-02569-5. Epub 2019 Sep 25.
• [50] 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.
• [51] 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.
• [52] Differential expression of PARK2 splice isoforms in an in vitro model of dopaminergic-like neurons exposed to toxic insults mimicking Parkinson's disease. J Cell Biochem. 2018 Jan;119(1):1062-1073. doi: 10.1002/jcb.26274. Epub 2017 Aug 23.
• [53] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
• [54] Reduced expression of PARK2 in manganese-exposed smelting workers. Neurotoxicology. 2017 Sep;62:258-264. doi: 10.1016/j.neuro.2017.08.006. Epub 2017 Aug 18.
• [55] PINK1/Parkin-mediated mitophagy alleviates chlorpyrifos-induced apoptosis in SH-SY5Y cells. Toxicology. 2015 Aug 6;334:72-80.
• [56] Lead (Pb) induced ATM-dependent mitophagy via PINK1/Parkin pathway. Toxicol Lett. 2018 Jul;291:92-100. doi: 10.1016/j.toxlet.2018.04.012. Epub 2018 Apr 13.
• [57] PINK1/Parkin-mediated mitophagy was activated against 1,4-Benzoquinone-induced apoptosis in HL-60 cells. Toxicol In Vitro. 2018 Aug;50:217-224. doi: 10.1016/j.tiv.2018.03.002. Epub 2018 Mar 20.
• [58] Cannabinoid CP55940 selectively induces apoptosis in Jurkat cells and in ex vivo T-cell acute lymphoblastic leukemia through H(2)O(2) signaling mechanism. Leuk Res. 2020 Aug;95:106389. doi: 10.1016/j.leukres.2020.106389. Epub 2020 May 26.
• [59] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.