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Aurora Kinases: Shining Lights on the Therapeutic Horizon?

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Aurora Kinases: Shining Lights on the Therapeutic Horizon? Oncogene (2005) 24, 5005–5015 & 2005 Nature Publishing Group All rights reserved 0950-9232/05 $30.00 www.nature.com/onc REVIEW Aurora kinases: shining lights on the therapeutic horizon? Paul D Andrews*,1 1Division of Gene Regulation and Expression, Wellcome Trust Biocentre, University of Dundee, Dundee, DD1 5EH, UK The Aurora kinases have been implicated in tumorigenesis to ensure accurate chromosome segregation and timely and are important regulators of diverse cell cycle events, cytokinesis. The approximate execution points of ranging from the entry into mitosis,centrosome function, Aurora A and B are shown in Figure 2. Aurora C’s mitotic spindle formation,chromosome biorientation and regulation and localization have remained obscure until segregation,and cytokinesis. The recent identification of recently (Li et al., 2004b; Sasai et al., 2004) and its real novel binding partners and key downstream effectors, function is unknown. together with new small-molecule inhibitors that display With over protein 500 kinases in the human genome efficacy against tumours,heralds an upsurge of interest in grouped into at least 20 structurally related families, the these critical kinases. This review details new develop- specificity of kinase inhibitors is a critical concern when ments in the field and analyses the potential of Aurora administrated in therapy. However, the recognition that kinases as anticancer targets. the selective inhibition of individual protein kinases is Oncogene (2005) 24, 5005–5015. doi:10.1038/sj.onc.1208752 not only possible, but has therapeutic efficacy (as exemplified by the success of the Bcl-Abl kinase Keywords: Aurora kinase; microtubule; spindle inhibitor, Gleevec, for the treatment of chronic myeloid checkpoint; centrosome; kinetochore; therapy leukemia) has led to a huge interest in the development of kinase inhibitors for cancer therapy. Here, I review recent advances in our understanding of Aurora kinase function, critically assess how detailed knowledge of their function could be utilized in cancer Introduction therapy and go on to discuss whether the Aurora kinases are indeed suitable targets for therapeutic intervention. Many fundamental processes in cancer cells are regu- lated by protein phosphorylation: kinases regulate the cell’s response to DNA damage, control DNA replica- Aurora A: cancer,centrosomes and the p53 connection tion, regulate entry into, passage through and exit from mitosis, and ensure accurate chromosome segregation; The human Aurora A gene, STK15, resides in a region they monitor nutrient availability and control cell of the genome (20q13.2) often amplified in certain growth pathways; and they regulate apoptosis and cancers (Bar-Shira et al., 2002). Aurora A overexpres- hence govern a cell’s commitment either to live or to die. sion occurs in a high proportion of breast, colorectal In metazoans, there are three highly related Aurora and gastric cancers (Tanaka et al., 1999; Sakakura kinases: Aurora A, B and C (reviewed in Andrews et al., et al., 2001; Goepfert et al., 2002; Gritsko et al., 2003; 2003; Carmena and Earnshaw, 2003; Brown et al., Moreno-Bueno et al., 2003; Fraizer et al., 2004; Jeng 2004). Despite their relatedness at the sequence level, the et al., 2004; Kamada et al., 2004; Tong et al., 2004). localization and functions of Aurora A and B are largely While these data are largely correlative, more compel- non-overlapping. Aurora A is localized at the centro- ling was the observation that overexpression of a some from the time of centrosome duplication through constitutively active mutant of Aurora A in rat1 cells to mitotic exit and regulates centrosome function. In led to neoplastic transformation, suggesting Aurora A is contrast, Aurora B is localized to inner-centromeric a bona fide oncogene (Bischoff et al., 1998). However, in chromatin from prophase until the metaphase–anaphase a recent report, controlled overexpression of Aurora A transition, whereupon it is relocalized to both the (STK6) in mice led to mitotic defects and mammary microtubules in the spindle midzone (and the cell cortex hyperplasia, but not malignant transformation (Zhang at the cleavage furrow) during telophase, ending up in et al., 2004). Aurora A was also recently shown to be a the midbody throughout cytokinesis (see Figure 1; low-penetrance skin tumour-susceptibility gene, with an reviewed in Andrews et al., 2003; Carmena and Earn- allelic variant (Ile31), frequently found amplified, whose shaw, 2003; Meraldi et al., 2004). Such behaviour marks presence was correlated with aneuploidy in human colon out Aurora B as a canonical ‘chromosome passenger’ tumour cells, with the Ile31 allele transforming rat1 cells protein (Earnshaw and Cooke, 1991), whose function is more potently than the more common Phe31 allele (Ewart-Toland et al., 2003). A separate study also found *Correspondence: PD Andrews; E-mail: [email protected] a correlation between the Ile31 allele and the riskof Aurora kinases: shining lights on the therapeutic horizon? PD Andrews 5006 Figure 1 Localization of Aurora A and B. Aurora A and B localize to different cellular structures. Aurora A localization to centrosome/spindle poles in metaphase and telophase (upper panels). Aurora B localization to the inner centromere from prometaphase to metaphase and then the spindle midzone microtubules in late anaphase/telophase (lower panels) and in the midbody during cytokinesis (not shown) of Aurora A levels (Mao et al., 2004). Further evidence pointing to a complexity in the regulation of Aurora levels comes from a recent study in rats, where estrogen was shown to lead to increases in Aurora A protein and mRNA levels, centrosome amplification, chromosome instability and ultimately to breast cancer (Li et al., 2004a). Aurora A’s role in centrosome function and duplica- tion is well established, yet still poorly understood (reviewed by Andrews et al., 2003; Meraldi et al., 2004). Disruption of Aurora A function delocalizes several components of the centrosome. Aurora A phosphor- ylates and recruits microtubule-associated proteins such as the kinesin Eg5 (Giet et al., 1999) and the acidic coiled-coil protein, TACC (Giet et al., 2002; Bellanger and Gonczy, 2003; Conte et al., 2003) to the centrosome. Recently, the human Lats2 tumour-suppressor protein Figure 2 Aurora kinase cell cycle execution points and substrates. was also shown to be recruited to the centrosome via Schematic diagram illustrating the known execution points and Aurora A-mediated phosphorlyation (Toji et al., 2004). substrates of Aurora A and B across the cell cycle. The substrates Aurora A appears to control entry into mitosis by phosphorylated in each phase of the cell cycle are color coded: regulating either the association of the cell cycle orange circles indicate Aurora A substrates and green circles indicate Aurora B substrates. Ipl1p substrates are indicated as a machinery with centrosomes, or possibly even directly double green and orange line (Hirota et al., 2003; Dutertre et al., 2004). Aurora A binds and phosphorylates the breast cancer-associated gene product, BRCA1, in vitro and in vivo and regulates breast carcinoma (Sun et al., 2004). Aurora A over- its function (Ouchi et al., 2004). Aurora A also regulates expression can occur because of gene amplification, human telomerase reverse transcriptase mRNA levels transcriptional induction or post-translational stabiliza- through c-myc, in ovarian and breast epithelial carcino- tion (Farruggio et al., 1999; Crane et al., 2004). Indeed, mas (Yang et al., 2004b). The inter-relationship bet- in a recent study the p53-dependent loss of the tumour ween all these pathways is, however, still obscure (see suppressor ubiquitin ligase, hCDC4 led to a stabilization Figure 3). Oncogene Aurora kinases: shining lights on the therapeutic horizon? PD Andrews 5007 Aurora A regulation is complex and involves the become attached to microtubules emanating from interplay between the small GTPase Ran and the spindle opposite spindle poles in a process known as biorienta- protein TPX2 as well as regulatory input from the type-1 tion (reviewed by Andrews et al., 2003; see Figure 4). protein phosphatase, PP1 (reviewed by Andrews et al., Errors in biorientation lead to CIN. Commonly 2003; Gruss and Vernos, 2004). Ran releases TPX2 from encountered errors include merotelic attachments (one importins a and b allowing TPX2 to bind Aurora A, kinetochore attached to microtubules from both poles) targeting it to spindle microtubules at the pole. TPX2 and syntelic attachments (both kinetochores attached to activates Aurora A activity by stimulating Aurora A microtubules from the same pole), as illustrated in autophosphorylation and by protecting it from the Figure 4. The cell’s surveillance mechanisms (check- inhibitory action of PP1 (Eyers et al., 2003; Tsai et al., points; discussed below) that monitor the attachment 2003). The crystal structure of activated Aurora A in and biorientation state of each chromosome give complex with a TPX2 fragment showed TPX2 binding is correction pathways sufficient time to ensure that all sufficient to allow autophosphorylation of the two chromosomes are configured properly, and thereby activatory T-loop theonines, allowing Aurora A to segregated equally in anaphase. Aurora B plays a key adopt a conformation similar to the ‘active’ conforma- role in this correction process. tion of other Ser/Thr kinases (Bayliss et al., 2003). This Aurora B (Ipl1p) phosphorylates a number of level of detailed knowledge is invaluable
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