Regulation of PLK4 levels and activity to ensure centriole number control

Dissertation presented to obtain a Ph.D degree in Cellular Biology

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.(...)

Apoio financeiro da FCT e do FSE no âmbito do Quadro Comunitário de apoio, BD nº SFRH/BD/33213/2007