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

Abstract

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.

Dual Targeting of WEE1 and PLK1 by AZD1775 Elicits Single Agent Cellular Anticancer Activity

“…No viable clone with a confirmed CRISPR-Cas9-mediated deletion of PLK1 was obtained consistent with an essential role for PLK1. 26, 27 A separate CRISPR-Cas9 clone, c WEE1 , retained WEE1 expression and CDK1 phosphorylation and thus constituted a suitable control. In order to evaluate specificity of the WEE1 knockout, clone cWEE1-KO 18 was stably reconstituted by expression of c-myc-tagged WEE1 , which was most pronounced in reconstitution clone RC9 (Figure 5C).…”

Squamous differentiation requires G2/mitosis slippage to avoid apoptosis

“…Cdk1 controls mitosis entry from G2 and its inactivation leads to mitosis failure [15,16]. Plk1 is required for proper chromosomal segregation during mitosis [17,18]. CDC20 binds to the anaphase-promoting complex (APC) and is required for satisfaction of the spindle assembly checkpoint (SAC) [19,20].…”

Plk1 overexpression induces chromosomal instability and suppresses tumor development

“…Plk1 was originally identified in Drosophila as a protein involved in spindle formation and further studies have suggested critical functions for this kinase in centrosome biology, spindle dynamics, chromosome segregation, and cytokinesis 12 , 13 . Genetic ablation of Plk1 or its chemical inhibition results in defective chromosome segregation commonly accompanied by cell cycle arrest or cell death in a variety of model organisms 13 , 14 . Plk1 induction has been proposed to play a role at early stages during the progression of certain carcinomas and its overexpression inversely correlates with the survival rate of patients with non-small cell lung, head and neck, and esophageal cancer, among others 15 – 17 .…”