Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice

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dc.authorid0000-0003-1827-9540
dc.authorid0000-0002-1423-0435
dc.contributor.authorGül, Şeref
dc.contributor.authorAkyel, Yasemin Kübra
dc.contributor.authorGül, Zeynep Melis
dc.contributor.authorIşın, Şafak
dc.contributor.authorÖzcan, Onur
dc.contributor.authorKorkmaz, Tuba
dc.contributor.authorSelvi, Saba
dc.contributor.authorDanış, İbrahim
dc.contributor.authorŞavluğ İpek, Özgecan
dc.contributor.authorAygenli, Fatih
dc.contributor.authorTaşkın, Ali Cihan
dc.contributor.authorAkarlar, Büşra Aytül
dc.contributor.authorÖzlü, Nurhan
dc.contributor.authorÖztürk, Nuri
dc.contributor.authorÖztürk, Narin
dc.contributor.authorÖzer Ünal, Durişehvar
dc.contributor.authorGüzel, Mustafa
dc.contributor.authorTürkay, Metin
dc.contributor.authorOkyar, Alper
dc.contributor.authorKavaklı, İbrahim Halil
dc.date.accessioned2022-11-25T13:27:50Z
dc.date.available2022-11-25T13:27:50Z
dc.date.issued2022
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Rejeneratif ve Restoratif Tıp Araştırmaları Merkezi (REMER)
dc.departmentİstanbul Medipol Üniversitesi, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, Tıbbi Farmakoloji Ana Bilim Dalı
dc.departmentİstanbul Medipol Üniversitesi, Uluslararası Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, Tıbbi Farmakoloji Ana Bilim Dalı
dc.description.abstractCryptochromes are negative transcriptional regulators of the circadian clock in mammals. It is not clear how reducing the level of endogenous CRY1 in mammals will affect circadian rhythm and the relation of such a decrease with apoptosis. Here, we discovered a molecule (M47) that destabilizes Cryptochrome 1 (CRY1) both in vitro and in vivo. The M47 selectively enhanced the degradation rate of CRY1 by increasing its ubiquitination and resulted in increasing the circadian period length of U2OS Bmal1-dLuc cells. In addition, subcellular fractionation studies from mice liver indicated that M47 increased degradation of the CRY1 in the nucleus. Furthermore, M47-mediated CRY1 reduction enhanced oxaliplatin-induced apoptosis in Ras-transformed p53 null fibroblast cells. Systemic repetitive administration of M47 increased the median lifespan of p53?/? mice by ~25%. Collectively our data suggest that M47 is a promising molecule to treat forms of cancer depending on the p53 mutation.
dc.description.sponsorshipTurkiye Cumhuriyeti Kalkinma Bakanligien_US
dc.identifier.citationGül, Ş., Akyel, Y. K., Gül, Z. M., Işın, Ş., Özcan, O., Korkmaz, T. ... Kavaklı, İ. H. (2022). Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice. Nature Communications, 13(1). https://doi.org/10.1038/s41467-022-34582-1
dc.identifier.doi10.1038/s41467-022-34582-1
dc.identifier.issn2041-1723
dc.identifier.issue1
dc.identifier.pmid36347873
dc.identifier.scopus2-s2.0-85141639395
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1038/s41467-022-34582-1
dc.identifier.urihttps://hdl.handle.net/20.500.12511/10029
dc.identifier.volume13
dc.identifier.wos000885370100009en_US
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorŞavluğ İpek, Özgecan
dc.institutionauthorGüzel, Mustafa
dc.language.isoen
dc.publisherNature Research
dc.relation.ispartofNature Communicationsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.relation.tubitakinfo:eu-repo/grantAgreement/TUBITAK/SOBAG/215S021
dc.rightsAttribution 4.0 International*
dc.rightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.subjectSmall Molecule
dc.subjectp53 Knockout Mice
dc.subjectCryptochrome
dc.titleDiscovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice
dc.typeArticle

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