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dc.contributor.authorSinha, Debottam
dc.contributor.authorNag, Purba
dc.contributor.authorNanayakkara, Devathri
dc.contributor.authorDuijf, Pascal HG
dc.contributor.authorBurgess, Andrew
dc.contributor.authorRaninga, Prahlad
dc.contributor.authorSmits, Veronique AJ
dc.contributor.authorBain, Amanda L
dc.contributor.authorSubramanian, Goutham
dc.contributor.authorWall, Meaghan
dc.contributor.authorFinnie, John W
dc.contributor.authorKalimutho, Murugan
dc.contributor.authorKhanna, Kum Kum
dc.date.accessioned2021-02-16T04:51:16Z
dc.date.available2021-02-16T04:51:16Z
dc.date.issued2020
dc.identifier.issn2399-3642en_US
dc.identifier.doi10.1038/s42003-020-01304-6en_US
dc.identifier.urihttp://hdl.handle.net/10072/402219
dc.description.abstractHigh expression of centrosomal protein CEP55 has been correlated with clinico-pathological parameters across multiple human cancers. Despite significant in vitro studies and association of aberrantly overexpressed CEP55 with worse prognosis, its causal role in vivo tumorigenesis remains elusive. Here, using a ubiquitously overexpressing transgenic mouse model, we show that Cep55 overexpression causes spontaneous tumorigenesis and accelerates Trp53+/- induced tumours in vivo. At the cellular level, using mouse embryonic fibroblasts (MEFs), we demonstrate that Cep55 overexpression induces proliferation advantage by modulating multiple cellular signalling networks including the hyperactivation of the Pi3k/Akt pathway. Notably, Cep55 overexpressing MEFs have a compromised Chk1-dependent S-phase checkpoint, causing increased replication speed and DNA damage, resulting in a prolonged aberrant mitotic division. Importantly, this phenotype was rescued by pharmacological inhibition of Pi3k/Akt or expression of mutant Chk1 (S280A) protein, which is insensitive to regulation by active Akt, in Cep55 overexpressing MEFs. Moreover, we report that Cep55 overexpression causes stabilized microtubules. Collectively, our data demonstrates causative effects of deregulated Cep55 on genome stability and tumorigenesis which have potential implications for tumour initiation and therapy development.en_US
dc.description.peerreviewedYesen_US
dc.languageEnglishen_US
dc.publisherNature Publishing Groupen_US
dc.relation.ispartofpagefrom593en_US
dc.relation.ispartofissue1en_US
dc.relation.ispartofjournalCommunications Biologyen_US
dc.relation.ispartofvolume3en_US
dc.subject.fieldofresearchBiological Sciencesen_US
dc.subject.fieldofresearchcode06en_US
dc.subject.keywordsScience & Technologyen_US
dc.subject.keywordsLife Sciences & Biomedicineen_US
dc.subject.keywordsBiologyen_US
dc.subject.keywordsMultidisciplinary Sciencesen_US
dc.subject.keywordsLife Sciences & Biomedicine - Other Topicsen_US
dc.titleCep55 overexpression promotes genomic instability and tumorigenesis in miceen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Articlesen_US
dcterms.bibliographicCitationSinha, D; Nag, P; Nanayakkara, D; Duijf, PHG; Burgess, A; Raninga, P; Smits, VAJ; Bain, AL; Subramanian, G; Wall, M; Finnie, JW; Kalimutho, M; Khanna, KK, Cep55 overexpression promotes genomic instability and tumorigenesis in mice, Communications Biology, 2020, 3 (1), pp. 593en_US
dcterms.dateAccepted2020-09-17
dcterms.licensehttp://creativecommons.org/licenses/by/4.0/en_US
dc.date.updated2021-02-16T04:48:29Z
dc.description.versionVersion of Record (VoR)en_US
gro.rights.copyright© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.en_US
gro.hasfulltextFull Text
gro.griffith.authorKhanna, Kum K.


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