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On the Role of Aurora-A in Centrosome Function

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On the Role of Aurora-A in Centrosome Function Oncogene (2002) 21, 6175 – 6183 ª 2002 Nature Publishing Group All rights reserved 0950 – 9232/02 $25.00 www.nature.com/onc On the role of aurora-A in centrosome function Ste´ phanie Dutertre1, Simon Descamps1 and Claude Prigent*,1 1Groupe Cycle Cellulaire, UMR 6061 Ge´ne´tique et de´veloppement, CNRS-Universite´ de Rennes I, IFR 97 Ge´nomique Fonctionnelle et Sante´, Faculte´ de Me´decine, 2 avenue du Pr Leon Bernard, CS 34317, 35043 Rennes cedex, France Mammalian aurora-A belongs to a multigenic family of 1998). Aurora-B is a chromosome passenger involved mitotic serine/threonine kinases comprising two other in cytokinesis and chromosome architecture (Adams et members: aurora-B and aurora-C. In this review we will al., 2000, 2001; Giet and Glover, 2001). Aurora-A is a focus on aurora-A that starts to localize to centrosomes centrosome kinase which function is not yet fully only in S phase as soon as centrioles have been understood. We must say here that although mamma- duplicated, the protein is then degraded in early G1. lian genomes encode for three different aurora kinases, Works in various organisms have revealed that the C. elegans and D. melanogaster genomes encodes for kinase is involved in centrosome separation, duplication aurora-A and aurora-B paralogue whereas the yeast and maturation as well as in bipolar spindle assembly genomes S. cerevisiae and S. pombe encode for only and stability. Aurora kinases are found in all organisms one aurora kinase (Chan and Botstein, 1993; Petersen in which their function has been conserved throughout et al., 2001). Although this is only speculation, it seems evolution, namely the control of chromosome segrega- that at least for yeast the functions of both the tion. In human, aurora-A has focused a lot of attention, mammalian aurora-A and -B is fulfilled by a unique since its overexpression has been found to be correlated kinase, suggesting that functions have diverged with the grade of various solid tumours. Ectopic kinase throughout evolution. One must then take carefully overexpression in any culture cell line leads to polyploidy the functions described for the yeast aurora kinases and centrosome amplification. However, overexpression and take into account the different localization of of aurora-A in particular cell lines such as NIH3T3 is aurora-A and aurora-B in mammalian cells. For sufficient to induce growth on soft agar. Those instance, the yeast aurora substrates found to date transformed cells form tumours when implanted in are the Ndc10p kinetochore protein, and the histone immunodeficient mice, indicating that the kinase is an H3 chromosomal protein whose localization corre- oncogene. sponds to the mammalian aurora-B localization. The Oncogene (2002) 21, 6175 – 6183. doi:10.1038/sj.onc. phosphorylation state of Ndc10p in yeast controls the 1205775 spindle microtubules attachment to the chromosome kinetochore (Biggins et al., 1999; Sassoon et al., 1999). Keywords: aurora; cancer; centrosome; kinase In addition, although the exact function of serine 10 phosphorylation in H3 during mitosis remains contro- versial, it seems to be necessary for chromosome segregation. In multicellular eukaryotes histone H3 Introduction have been demonstrated to be an aurora-B substrate by RNA-mediated interference both in C. elegans (Hsu et The mammalian aurora-A has been first identified al., 2000) and in D. melanogaster (Adams et al., 2001; within the amplicon 20q13 frequently detected in Giet and Glover, 2001). Aurora-A phosphorylates the human breast tumours (Tanner et al., 1994, 1995). kinesin related protein Eg5 required for both centro- Only a partial cDNA encoding a protein kinase was some separation and spindle assembly and stability, isolated and named BTAK for Breast Tumour just like aurora-A (Giet et al., 1999a). The kinase also Activated Kinase (Sen et al., 1997). Few years later, phosphorylates CPEB protein (Cytoplasmique Poly- a Drosophila gene encoding a kinase homologue was adenylation Element Binding protein), and this identified and named aurora (Glover et al., 1995). phosphorylation induces polyadenylation of mRNA Many aurora kinases have then been found in various allowing translation during Xenopus oocyte maturation organisms giving birth to as many different confusing (Mendez et al., 2000). This mechanism seems to occur names as publications, and Erich Nigg proposed the locally within the spindle pole in the vicinity of the nomenclature aurora-A, -B and -C (Nigg, 2001). centrosome (Groisman et al., 2000). Recently the Aurora-C expression seems to be restricted to human TACC3 (Transforming Acidic Coiled Coil spermatogenesis at the time when cells assemble the protein number 3) has also been found to be two meiotic spindles (Hu et al., 2000; Tseng et al., phosphorylated by aurora-A. The function of this phosphorylation in D. melanogaster is to recruit the protein to the centrosome (Giet et al., 2002). This *Correspondence: C Prigent; E-mail: [email protected] might in fact be one of the major roles of aurora-A; Aurora and centrosome S Dutertre et al 6176 recruiting proteins on the centrosome to fulfil a local function, insuring centrosome maturation for instance (Berdnik and Knoblich, 2002; Hannak et al., 2001). In order to better understand what could be the function of aurora-A, in the first part of this review we will describe in a very simplistic way the behaviour and the function of the centrosome during cell cycle. We will then concentrate on the aurora-A kinase itself, its structure, localization and cell cycle behaviour. In a second part, we will focus on the four different functions attributed to aurora-A during cell cycle progression in various organisms. Finally, we will introduce the oncogenic potential of the kinase over- expression. Indeed, the main goal in current aurora-A research is to understand how its amplification leads to cell transformation. Aurora-A localizes to the centrosome The centrosome The centrosome in G1 can be schematically described as an organelle comprising three areas: the two centrioles, the connection between centrioles (the matrix) and the pericentriolar material (PCM) (Figure 1). The centriole is made of nine triplets of micro- tubules assembled around a ‘cartwheel’ of unknown composition to form a cylinder. The two centrioles are different, one old ‘mother’ (with appendages) and one young ‘daughter’. The matrix is composed of various proteins that connect the two centrioles in a flexible Figure 1 Localization area of aurora-A at the centrosome. The top panel shows a very simplistic scheme of a centrosome with manner. The composition of the PCM varies along the its two centrioles (in blue); the young one (light blue) and the cell cycle progression with proteins coming and leaving old one (dark blue) with its appendages (in grey). The connections this very active area. In mammalian cells, the major between the centrioles are represented by a green area and the function of the centrosome has long been thought to be pericentriolar material in red correspond to aurora-A localization. only a microtubule organizing centre (MTOC) organiz- The lower panel shows an image taken in a cell showing one cen- trosome (two centrioles) stained with GFP-centrin (green) and an ing the interphase microtubule network and the bipolar anti-aurora-A antibody (red) mitotic spindle. However, the centrosome, at least one of the centrioles, is also implicated in cytokinesis. Indeed, mammalian cells lacking centrosome can assemble a bipolar spindle, but are not able to divide from the end of S phase to the beginning of the G1 (Bornens, 2002). phase of the next cycle (Figure 2a,b). The three aurora kinases that show different cellular localization have a conserved catalytic domain (C- Aurora-A term) and a non-catalytic domain (N-term) different in During the G2 phase of the cell cycle aurora-A size and sequence. In the case of aurora-A, both GFP- colocalizes with g-tubulin in mammalian cells indicat- tagged domains localize to centrosomes. However, the ing that it is a centrosome protein (Gopalan et al., centrosome localization of the N-terminal domain 1997; Kimura et al., 1997; Roghi et al., 1998). The depends on the presence of microtubules (active protein is also found at the bipolar mitotic spindle mechanism) whereas the centrosome localization of poles. However, the immunodetection of aurora-A in the C-terminal domain is independent of microtubules cultured cells requires an absence of detergent indicat- (passive mechanism) (Giet and Prigent, 2001). Depoly- ing that the binding of the kinase to the centrosome is merization of the microtubules by nocodazole weak. At the electron microscopy level aurora-A is treatment does not remove aurora-A from the mainly found around the PCM (Roghi et al., 1998) and centrosome, indicating that its localization can be in GFP-centrin transformed cells aurora-A is clearly microtubule independent (Roghi et al., 1998). The detected in a quite large area around the two dots catalytic domain presumably localizes to centrosomes corresponding to the centrioles (Figure 1b and personal because of its affinity for the kinase substrates (Giet observation). The localization of aurora-A depends on and Prigent, 2001). However, its kinase activity is not the cell cycle: the protein is detected by indirect necessary for centrosome localization, since the kinase- immunofluorescence only on duplicated centrosomes, dead mutant localizes like the active one (Giet and Oncogene Aurora and centrosome S Dutertre et al 6177 Figure 2 Aurora-A and centrosome during cell cycle. (a) Scheme of centriole duplication, centrosome behaviour and aurora-A localization during cell cycle progression. The old (mother) centriole is in dark blue and the young (daughter) one in light blue. Aurora-A localization area is in red. (b) Indirect immunolocalization of aurora-A (red) in GFP-centrin (green) transfected cells. Three cells in different cell cycle phases were selected : G1 (top panel), S/G2 (middle panel) and metaphase (lower panel).
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