title: Over-expression of Plk4 induces centrosome amplification, loss of primary cilia and associated tissue hyperplasia in the mouse.
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.
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
authors.forename: Paula A
authors.initials: PA
authors.lastname: Coelho
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
authors.forename: Leah
authors.initials: L
authors.lastname: Bury
authors.affiliation: Department of Physiology, Development and Neuroscience, Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Marta N
authors.initials: MN
authors.lastname: Shahbazi
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK Centre for Stem Cells and Regenerative Medicine, King's College London, Floor 28, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Kifayathullah
authors.initials: K
authors.lastname: Liakath-Ali
authors.affiliation: Wellcome Trust Genome Campus, the Wellcome Trust Sanger Institute, Cambridge, Hinxton CB10 1SA, UK.
authors.forename: Peri H
authors.initials: PH
authors.lastname: Tate
authors.affiliation: Wellcome Trust Genome Campus, the Wellcome Trust Sanger Institute, Cambridge, Hinxton CB10 1SA, UK.
authors.forename: Sam
authors.initials: S
authors.lastname: Wormald
authors.affiliation: Henry Wellcome Building of Cancer and Developmental Biology, the Wellcome Trust/Cancer Research UK Gurdon Institute, Tennis Court Road, Cambridge CB2 1QN, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hindley
authors.affiliation: Henry Wellcome Building of Cancer and Developmental Biology, the Wellcome Trust/Cancer Research UK Gurdon Institute, Tennis Court Road, Cambridge CB2 1QN, UK.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Huch
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
authors.forename: Joy
authors.initials: J
authors.lastname: Archer
authors.affiliation: Wellcome Trust Genome Campus, the Wellcome Trust Sanger Institute, Cambridge, Hinxton CB10 1SA, UK.
authors.forename: William C
authors.initials: WC
authors.lastname: Skarnes
authors.affiliation: Department of Physiology, Development and Neuroscience, Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zernicka-Goetz
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK dmg25@hermes.cam.ac.uk.
authors.forename: David M
authors.initials: DM
authors.lastname: Glover
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D002502:Centrioles / Q000378:metabolism; D018385:Centrosome / Q000378:metabolism*; D002923:Cilia / Q000378:metabolism*; D000091344:Filaggrin Proteins; D006965:Hyperplasia / Q000378:metabolism*; D007381:Intermediate Filament Proteins / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D011498:Protein Precursors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D008565:Membrane Proteins; D011498:Protein Precursors; C064554:loricrin; C032253:involucrin; C088051:Plk4 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: Polo-like-kinase-4; centrosome amplification; pancreas; primary cilia; skin; tumour development