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https://hdl.handle.net/2440/129640
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Type: | Journal article |
Title: | Cep55 overexpression promotes genomic instability and tumorigenesis in mice. |
Author: | Sinha, D. Nag, P. Nanayakkara, D. Duijf, P.H.G. Burgess, A. Raninga, P. Smits, V.A.J. Bain, A.L. Subramanian, G. Wall, M. Finnie, J.W. Kalimutho, M. Khanna, K.K. |
Citation: | Communications Biology, 2020; 3(1):593-593 |
Publisher: | Nature Research |
Issue Date: | 2020 |
ISSN: | 2399-3642 2399-3642 |
Statement of Responsibility: | Debottam Sinha, Purba Nag, Devathri Nanayakkara, Pascal H. G. Duijf, Andrew Burgess, Prahlad Raninga ... et al. |
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 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. |
Keywords: | Lymph Nodes Cell Line Microtubules Fibroblasts Animals Mice, Transgenic Mice Cell Transformation, Neoplastic Disease Susceptibility Genomic Instability Cell Cycle Proteins Biopsy Immunohistochemistry Signal Transduction Mitosis Gene Expression Genotype Tumor Suppressor Protein p53 Proto-Oncogene Proteins c-akt Stress, Physiological Protein Stability Karyotype Biomarkers, Tumor Checkpoint Kinase 1 |
Rights: | © The Author(s) 2020. Open Access 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. |
DOI: | 10.1038/s42003-020-01304-6 |
Published version: | http://dx.doi.org/10.1038/s42003-020-01304-6 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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