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  • Cep55 overexpression promotes genomic instability and tumorigenesis in mice

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    Author(s)
    Sinha, Debottam
    Nag, Purba
    Nanayakkara, Devathri
    Duijf, Pascal HG
    Burgess, Andrew
    Raninga, Prahlad
    Smits, Veronique AJ
    Bain, Amanda L
    Subramanian, Goutham
    Wall, Meaghan
    Finnie, John W
    Kalimutho, Murugan
    Khanna, Kum Kum
    Griffith University Author(s)
    Khanna, Kum K.
    Year published
    2020
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    Abstract
    High 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 ...
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    High 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.
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    Journal Title
    Communications Biology
    Volume
    3
    Issue
    1
    DOI
    https://doi.org/10.1038/s42003-020-01304-6
    Copyright Statement
    © 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.
    Subject
    Biological sciences
    Science & Technology
    Life Sciences & Biomedicine
    Biology
    Multidisciplinary Sciences
    Life Sciences & Biomedicine - Other Topics
    Publication URI
    http://hdl.handle.net/10072/402219
    Collection
    • Journal articles

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