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Over-expression of Plk4 induces centrosome amplification, loss of primary cilia and associated tissue hyperplasia in the mouse

Coelho, Paula A. and Bury, Leah and Shahbazi, Marta N. and Liakath-Ali, Kifayathullah and Tate, Peri H. and Wormald, Sam and Hindley, Christopher J. and Huch, Meritxell and Archer, Joy and Skarnes, William C. and Zernicka-Goetz, Magdalena and Glover, David M. (2015) Over-expression of Plk4 induces centrosome amplification, loss of primary cilia and associated tissue hyperplasia in the mouse. Open Biology, 5 (12). Art. No. 150209. ISSN 2046-2441. PMCID PMC4703062. https://resolver.caltech.edu/CaltechAUTHORS:20190405-170315456

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Abstract

To address the long-known relationship between supernumerary centrosomes and cancer, we have generated a transgenic mouse that permits inducible expression of the master regulator of centriole duplication, Polo-like-kinase-4 (Plk4). Over-expression of Plk4 from this transgene advances the onset of tumour formation that occurs in the absence of the tumour suppressor p53. Plk4 over-expression also leads to hyperproliferation of cells in the pancreas and skin that is enhanced in a p53 null background. Pancreatic islets become enlarged following Plk4 over-expression as a result of equal expansion of α- and β-cells, which exhibit centrosome amplification. Mice overexpressing Plk4 develop grey hair due to a loss of differentiated melanocytes and bald patches of skin associated with a thickening of the epidermis. This reflects an increase in proliferating cells expressing keratin 5 in the basal epidermal layer and the expansion of these cells into suprabasal layers. Such cells also express keratin 6, a marker for hyperplasia. This is paralleled by a decreased expression of later differentiation markers, involucrin, filaggrin and loricrin. Proliferating cells showed an increase in centrosome number and a loss of primary cilia, events that were mirrored in primary cultures of keratinocytes established from these animals. We discuss how repeated duplication of centrioles appears to prevent the formation of basal bodies leading to loss of primary cilia, disruption of signalling and thereby aberrant differentiation of cells within the epidermis. The absence of p53 permits cells with increased centrosomes to continue dividing, thus setting up a neoplastic state of error prone mitoses, a prerequisite for cancer development.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1098/rsob.150209DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703062/PubMed CentralArticle
ORCID:
AuthorORCID
Coelho, Paula A.0000-0003-0614-7575
Bury, Leah0000-0002-6218-2837
Shahbazi, Marta N.0000-0002-1599-5747
Zernicka-Goetz, Magdalena0000-0002-7004-2471
Glover, David M.0000-0003-0956-0103
Additional Information:© 2015 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited. Received: 22 October 2015. Accepted: 2 December 2015. P.A.C. is supported by a Program Grant from Cancer Research UK to D.M.G. L.B. is the recipient of a Cancer Research UK research studentship from Cambridge Cancer Centre. M.S. is supported by an EMBO Fellowship. M.H. is a Wellcome Trust Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society and receiving core support grant from the Wellcome Trust and Cancer Research UK to the Wellcome Trust—Cancer Research UK Gurdon Institute. W.C.S. is supported by core funding to the Wellcome Trust Sanger Institute; M.Z.G. holds a Wellcome Trust Senior Fellowship. We declare we have no competing interests.
Funders:
Funding AgencyGrant Number
Cancer Research UKUNSPECIFIED
European Molecular Biology Organization (EMBO)UNSPECIFIED
Wellcome TrustUNSPECIFIED
Royal SocietyUNSPECIFIED
Subject Keywords:primary cilia, Polo-like-kinase-4, skin, tumour development, centrosome amplification, pancreas
Issue or Number:12
PubMed Central ID:PMC4703062
Record Number:CaltechAUTHORS:20190405-170315456
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190405-170315456
Official Citation:Over-expression of Plk4 induces centrosome amplification, loss of primary cilia and associated tissue hyperplasia in the mouse Paula A. Coelho, Leah Bury, Marta N. Shahbazi, Kifayathullah Liakath-Ali, Peri H. Tate, Sam Wormald, Christopher J. Hindley, Meritxell Huch, Joy Archer, William C. Skarnes, Magdalena Zernicka-Goetz and David M. Glover Open BiologyVolume 5, Issue 12 Published:01 December 2015 https://doi.org/10.1098/rsob.150209
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:94541
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:09 Apr 2019 21:42
Last Modified:03 Oct 2019 21:04

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