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Regulation of PLK4 levels and activity to ensure centriole number control
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The centrosome is the major microtubule-organizing center of animal
cells. It is involved in the regulation of cell motility and polarity in interphase
and the organization of the mitotic spindle in mitosis. Each centrosome is
composed by two centrioles, a mother and a daughter, that recruit and
organize a protein-rich matrix, the pericentriolar material (PCM). The PCM
harbors factors involved in microtubule nucleation and anchoring. Centriole
duplication is a highly controlled process that must occur once and only once
per cell cycle. The first visible signs of centriole duplication occur in G1/S
phases of the cell cycle, in concert with DNA replication and with the growth
of one daughter per mother centriole (Bettencourt-Dias and Glover, 2007;
Nigg, 2007). Failure to properly control centriole duplication leads to
centrosome amplification and abnormal chromosome segregation (Ganem et
al., 2009). In fact centrosome amplification is a common characteristic of
many cancers (Lingle et al., 2002, 1998; Pihan et al., 2003, 1998; Giehl et al.,
2005; Bettencourt-Dias et al., 2011; Godinho et al., 2009).
The PLK4 kinase has been identified as a master regulator of this
process as in its absence centrioles fail to duplicate, while increased PLK4
levels lead to centriole amplification (Kleylein-Sohn et al., 2007; Rodrigues-
Martins et al., 2007; Peel et al., 2007; Bettencourt-Dias et al., 2005;
Habedanck et al., 2005). Thus PLK4 protein levels and kinase activity must
be tightly regulated in order to avoid blocking centriole duplication or centriole
amplification. Given the importance of PLK4 for this process, we sought to
investigate how PLK4 protein levels and activity are regulated in the cell cycle
and how this impinges on centriole duplication.(...)
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Dissertation presented to obtain a Ph.D degree in Cellular Biology
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Universidade Nova de Lisboa. Instituto de Tecnologia Química e Biológica