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Habedanck, Robert (2006): The Human Polo-like Kinase 4 is a Regulator of Centrosome Duplication. Dissertation, LMU München: Faculty of Biology
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Abstract

Polo-like kinase 4 (Plk4), also known as Snk/Fnk-akin kinase (Sak), is the most structurally divergent member of the Polo-like kinase family (Fode et al., 1994; Leung et al., 2002) and has been associated with cell proliferation (Fode et al., 1994). Most importantly, Plk4-/- mice were found to be embryonically lethal whereas heterozygous Plk+/- mice exhibited an increased incidence of tumorigenesis (Hudson et al., 2001; Ko et al., 2005). However, very little data has been reported on the function of human Plk4. Here, we embarked on a functional characterisation of human Plk4 in cultured cells. This kinase localised to the centrosome throughout the cell cycle, and overexpression studies revealed that an excess of wild type Plk4 induced the overduplication of centrioles in cells. This process was dependent on the cyclin-dependent kinase (Cdk) 2 in addition to CP110 and human Sas-6, two proteins shown to be involved in centriole duplication (Chen et al., 2002b; Leidel et al., 2005). Conversely, depletion of endogenous Plk4 resulted in an inhibition of centriole duplication leading to a loss of centrioles from dividing cells. These data from gain-of-function and loss-of-function experiments demonstrated that Plk4 is an essential regulator of centriole duplication. Further microscopic studies revealed that excess Plk4 activity resulted in the formation of rosette-like structures around centrioles. These structures recruited CPAP which is the human homologue of Sas-4, a protein required for centriole duplication in the nematode worm (Caenorhabditis elegans). We propose that these structures represent centriole precursors. The study presented here is a starting point for further work. The identification of Plk4 as a central regulator of centriole duplication will allow the characterisation of upstream and downstream regulatory pathways, whereas a continued search for interaction partners should resolve the function of this kinase. In particular, the analysis of rosette-like centriole precursors is a promising avenue to provide insights into the mechanism of centriole duplication.