Genetic depletion of Polo-like kinase 1 leads to embryonic lethality due to mitotic aberrancies

Polo‐like kinase 1 (PLK1) is a serine/threonine kinase that plays multiple and essential roles during the cell division cycle. Its inhibition in cultured cells leads to severe mitotic aberrancies and cell death. Whereas previous reports suggested that Plk1 depletion in mice leads to a non‐mitotic ar...

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Bibliographic Details
Published in:BioEssays 2016-07, Vol.38 (S1), p.S96-S106
Main Authors: Wachowicz, Paulina, Fernández-Miranda, Gonzalo, Marugán, Carlos, Escobar, Beatriz, de Cárcer, Guillermo
Format: Article
Language:English
Subjects:
Animal models
Animal physiology
Animals
Cell cycle
Cell Cycle Proteins - physiology
Cell death
Cell division
Chromosome Segregation
Chromosomes
Clinical trials
Cytokinesis
Depletion
development
Embryos
Female
Kinases
Lethality
Male
Mice
Mitosis
Polo-Like Kinase 1
Protein Serine-Threonine Kinases - physiology
Protein-serine/threonine kinase
Proto-Oncogene Proteins - physiology
Spindle Apparatus - metabolism
Spindle Apparatus - physiology
spindle dynamics
Spindles
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Summary:Polo‐like kinase 1 (PLK1) is a serine/threonine kinase that plays multiple and essential roles during the cell division cycle. Its inhibition in cultured cells leads to severe mitotic aberrancies and cell death. Whereas previous reports suggested that Plk1 depletion in mice leads to a non‐mitotic arrest in early embryos, we show here that the bi‐allelic Plk1 depletion in mice certainly results in embryonic lethality due to extensive mitotic aberrations at the morula stage, including multi‐ and mono‐polar spindles, impaired chromosome segregation and cytokinesis failure. In addition, the conditional depletion of Plk1 during mid‐gestation leads also to severe mitotic aberrancies. Our data also confirms that Plk1 is completely dispensable for mitotic entry in vivo. On the other hand, Plk1 haploinsufficient mice are viable, and Plk1‐heterozygous fibroblasts do not harbor any cell cycle alterations. Plk1 is overexpressed in many human tumors, suggesting a therapeutic benefit of inhibiting Plk1, and specific small‐molecule inhibitors for this kinase are now being evaluated in clinical trials. Therefore, the different Plk1 mouse models here presented are a valuable tool to reexamine the relevance of the mitotic kinase Plk1 during mammalian development and animal physiology. Two different mouse strains, a classical gene‐trapping KO and a conditional KO by Cre recombinase excision, demonstrate that the mitotic kinase Plk1 is essential at any stage of the embryonic development, and its depletion leads to mitotic aberrancies and embryonic death. Instead, Plk1 haploinsufficient mice do not show any alteration.
ISSN:0265-9247
1521-1878
DOI:10.1002/bies.201670908