Please use this identifier to cite or link to this item: http://hdl.handle.net/123456789/1164
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dc.contributor.authorSengupta, Sagar-
dc.contributor.authorTripathi, Vivek-
dc.contributor.authorKaur, Ekjot-
dc.contributor.authorKharat, Suhas Sampat-
dc.contributor.authorHussain, Mansoor-
dc.contributor.authorDamodaran, Arun Prasath-
dc.contributor.authorKulshrestha, Swati-
dc.date.accessioned2021-03-01T10:24:08Z-
dc.date.available2021-03-01T10:24:08Z-
dc.date.issued2019-09-
dc.identifier.urihttp://hdl.handle.net/123456789/1164-
dc.description.abstractThe gene encoding the tumor suppressor p53 is mutated in most cancers. p53 expression is known to be tightly controlled by several E3 ligases. Here, we show that F-box and WD repeat domain-containing 7α (FBW7α), the substrate-recognition component of the SCFFBW7 multiprotein E3 ligase complex, targets both WT and tumor-derived mutants of p53 for proteasomal degradation in multiple human cancer cell lines (HCT116 and U2OS). We found that lack of FBW7α stabilizes p53 levels, thereby increasing its half-life. p53 ubiquitylation and subsequent degradation require the F-box and the C-terminal WD40 repeats in FBW7α. The polyubiquitylation of p53 occurred via Lys-48 linkage and involved phosphorylation on p53 at Ser-33 and Ser-37 by glycogen synthase kinase 3β (GSK3β) and DNA-dependent protein kinase (DNA-PK), respectively. These phosphorylation events created a phosphodegron that enhanced p53 binding to FBW7α, allowing for the attachment of polyubiquitin moieties at Lys-132 in p53. FBW7α-dependent p53 polyubiquitylation apparently occurred during and immediately after DNA double-strand breaks induced by either doxorubicin or ionizing radiation. Accordingly, in cells lacking FBW7α, p53 induction was enhanced after DNA damage. Phosphodegron-mediated polyubiquitylation of p53 on Lys-132 had functional consequences, with cells in which FBW7α-mediated p53 degradation was abrogated exhibiting enhancement of their tumorigenic potential. We conclude that p53, which previously has been reported to transactivate FBW7, is also targeted by the same E3 ligase for degradation, suggesting the presence of a regulatory feedback loop that controls p53 levels and functions during DNA damage.en_US
dc.language.isoenen_US
dc.publisherThe American Society for Biochemistry and Molecular Biology, Incen_US
dc.titleAbrogation of FBW7 -dependent p53 degradation enhances p53’s function as a tumor suppressoren_US
dc.typeArticleen_US
dc.journalJournal of Biological Chemistryen_US
dc.volumeno294en_US
dc.issueno36en_US
dc.pages13224-13232en_US
Appears in Collections:Signal Transduction-II, Publications

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