Evidence that melatonin downregulates Nedd4-1 E3 ligase and its role in cellular survival

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dc.authorid0000-0002-1064-7989
dc.authorid0000-0002-9476-8488
dc.authorid0000-0002-5072-132X
dc.authorid0000-0002-6242-3709
dc.authorid0000-0001-6494-8923
dc.contributor.authorYalçın, Esra
dc.contributor.authorBeker, Mustafa Çağlar
dc.contributor.authorTürkseven, Şeyma
dc.contributor.authorÇağlayan, Berrak
dc.contributor.authorGürel, Büşra
dc.contributor.authorKılıç, Ülkan
dc.contributor.authorÇağlayan, Ahmet Burak
dc.contributor.authorKalkan, Rabia
dc.contributor.authorBaykal, Ahmet Tarık
dc.contributor.authorKeleştemur, Taha
dc.contributor.authorKılıç, Ertuğrul
dc.date.accessioned2019-12-26T07:00:49Z
dc.date.available2019-12-26T07:00:49Z
dc.date.issued2019
dc.departmentİstanbul Medipol Üniversitesi, Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Fizyoloji Ana Bilim Dalı
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Rejeneratif ve Restoratif Tıp Araştırmaları Merkezi (REMER)
dc.departmentİstanbul Medipol Üniversitesi, Uluslararası Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Tıbbi Biyoloji Ana Bilim Dalı
dc.departmentİstanbul Medipol Üniversitesi, Uluslararası Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Fizyoloji Ana Bilim Dalı
dc.description.abstractIndolamine melatonin structurally resembles non-covalent proteasome inhibitors; however, the role of ubiquitin proteasome system (UPS) in neuronal survival and how melatonin carries out UPS inhibition remain largely unknown. With the use of melatonin treated cells, we evaluated the expression of Nedd4-1, an E3 ligase, how melatonin regulates its activity and its relationship with neuronal survival. Nedd4-1 was upregulated in the hypoxic condition in both control and Nedd4-1 overexpressed cells and melatonin treatment reversed its expression in both normoxic and hypoxic conditions, which was associated with increased cellular survival. Melatonin had no effect on the expression of Nedd4-1 at mRNA level. However, when melatonin was administered along with protein synthesis inhibitor cycloheximide, protein level of Nedd4-1 was further reduced, indicating that melatonin possibly downregulates Nedd4-1 after its synthesis. Notably, co-immunoprecipitation analyses followed by Liquid chromatography Mass Spectrometry (LC-MS/MS) revealed that melatonin may dissociate ribosomal proteins, such as RS19, RL23A, and nucleophosmin from Nedd4-1, while 40S ribosomal protein S7 and 60S ribosomal protein L35 came into contact with Nedd4-1 upon melatonin treatment. By using IPA analyses, we obtained further data indicated novel target molecules of melatonin in hypoxic conditions, including OTOF, SF3B2, IPO5, ST13, FGFR3, Mxl/Mx2, playing roles in RNA splicing and trafficking, growth factor and interferon signaling. Here, we described a new insight into the role of melatonin in UPS functioning by proposing a molecular mechanism through which melatonin regulates Nedd4-1.
dc.identifier.citationYalçın, E., Beker, M. Ç., Türkseven, Ş., Çağlayan, B., Gürel, B., Kılıç, Ü. ... Kılıç, E. (2019). Evidence that melatonin downregulates Nedd4-1 E3 ligase and its role in cellular survival. Toxicology and Applied Pharmacology, 379. https://doi.org/10.1016/j.taap.2019.114686
dc.identifier.doi10.1016/j.taap.2019.114686
dc.identifier.issn0041-008X
dc.identifier.issn1096-0333
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1016/j.taap.2019.114686
dc.identifier.urihttps://hdl.handle.net/20.500.12511/4708
dc.identifier.volume379
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherAcademic Press Inc Elsevier Science
dc.relation.ispartofToxicology and Applied Pharmacologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/embargoedAccess
dc.subjectMelatonin
dc.subjectUbiquitin Proteosome System
dc.subjectNedd4-1
dc.subjectProteomic
dc.subjectProteasome
dc.subjectUbiquitin
dc.titleEvidence that melatonin downregulates Nedd4-1 E3 ligase and its role in cellular survival
dc.typeArticle

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