Review TRENDS in Cell Biology
5 May 2005
Chromosome Segregation and Aneuploidy series
Aurora kinases, aneuploidy and cancer,
a coincidence or a real link?
Régis Giet, Clotilde Petretti and Claude Prigent
CNRS UMR6061 Université de Rennes 1, Groupe Cycle Cellulaire, Equipe Labellisée LNCC, Université de Rennes 1, IFR140 GFAS,
Faculté de Médecine, 2 Avenue du Pr Léon Bernard, CS 3417, Rennes cedex, France
As Aurora kinases are overexpressed in a large number of
cancers, and ectopic expression of Aurora generates
polyploid cells containing multiple centrosomes, it has
been tempting to suggest that Aurora overexpression
provokes genetic instability underlying the tumori-
genesis. However, examination of the evidence suggests
a more complex relationship. Overexpression of Aurora-A
readily transforms rat-1 and NIH3T3 cells, but not primary
cells, whereas overexpression of Aurora-B induces meta-
stasis after implantation of tumors in nude mice. Why do
polyploid cells containing abnormal centrosome numbers
induced by Aurora not get eliminated at cell-cycle
checkpoints? Does this phenotype determine the origin
of cancer or does it only promote tumor progression?
Would drugs against aurora family members be of any
help for cancer treatment? These and related questions
are addressed in this review (which is part of the
Chromosome Segregation and Aneuploidy series).
Introduction
The main goal of a mitotic cell is to equally segregate its
chromosomes and centrosomes between two daughter
cells (Figure 1). As early as 1902, Theodore Boveri
predicted that mitotic abnormalities could lead to genetic
instability and cancer [1]. Indeed, during mitosis, a
spectacular reorganization of the cytoskeleton occurs
that builds a bipolar microtubule spindle that assures
proper segregation of chromosomes. Mitosis is progres-
sively readied throughout cell-cycle progression: a series
of precisely coordinated events must have occurred before
the G2–M transition occurs. By the end of S-phase, the cell
must have duplicated its centrosome and replicated its
DNA. At the end of prophase, the duplicated and matured
centrosomes must have become separated. During pro-
metaphase, the two centrosomes and the chromosomes
nucleate highly dynamic mitotic microtubules that
assemble a bipolar spindle [2]. During progression from
prometaphase to metaphase, the chromosomes must
become bi-orientated and aligned at the metaphase
plate. Bi-orientation is achieved by microtubule-organized
attachment of kinetochore pairs to opposite centrosomes.
During this process, the mitotic checkpoint is continu-
ously activated; it controls microtubule attachment to the
Corresponding author: Prigent, C. (claude.prigent@univ-rennes1.fr).
Available online 2 April 2005
www.sciencedirect.com 0962-8924/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tcb.2005.03.004
Vol.15 No.
kinetochores and tension. When these two conditions are
satisfied, the checkpoint signals are switched off, the
chromatids separate and anaphase proceeds. In telophase,
nuclear division occurs and the cell undergoes cytokinesis.
Finally, each daughter cell receives one set of chromo-
somes and one centrosome (Box 1).
Considering the complexity of mitosis, it is not surprising
that there are many mitotic defects that can lead to the
formation of aneuploid daughter cells. An aneuploid cell
possesses an altered content of DNA (abnormal number of
chromosomes). To give some examples, during mitosis, one
can easily imagine at least four ways to obtain an aneuploid
cell: (1) incorrect centrosome duplication during interphase
that can lead to the formation of multipolar spindles,
(2) improper centrosome separation, (3) defective cytokin-
esis and (4) chromosome mis-orientation (Figure 1).
Progression through mitosis depends on three main
regulatory mechanisms: protein localization, proteolysis
and phosphorylation. Cdk1 (cyclin-dependent kinase 1 or
p34cdc2), Plk1 (Polo-like kinase), Nek2 (NIMA-related
kinase 2) and Aurora kinases are the main mitotic protein
kinases known to date [3]. Aurora kinases are involved in
centrosome separation and maturation, spindle assembly
and stability, chromosome condensation, congression and
segregation, and cytokinesis [4]. In mammalian cells,
three aurora kinases have been identified, named Aurora-A,
-B and -C [3]. They possess a very conserved catalytic
domain and an N-terminal domain that varies in sequence
and in length [5,6]. It is thought that the different Aurora
kinases localize differentially and might perform different
functions during mitosis. However, all three human
kinases are overexpressed in many types of cancers, in
which polyploid cells containing multiple centrosomes are
observed. This review discusses how overexpression of
aurora kinases provokes the development of such a
phenotype, and whether this phenotype is key to onco-
genesis. Although many studies of Aurora kinases in
organisms such as yeasts, Drosophila, Caenorhabditis
elegans and Xenopus have greatly contributed to our
understanding of the functions of the kinases, we will only
use here the nomenclature Aurora-A, -B and -C and the
names of mammalian proteins whenever possible.
Aurora-A: a non residential centrosome kinase
Aurora-A kinase localizes on duplicated centrosomes from
the end of S phase to the beginning of the following G1
242 Review TRENDS in Cell Biology Vol.15 No.5 May 2005

2N
G1

2<N<4 S

4N 4N

G2

4N 4N

2N
G1
Three One One Two
aneuploid polyploid 2N polyploid aneuploid
cells cell cell cells
1 2 3 4
2 DIPLOID
CELLS

TRENDS in Cell Biology

Figure 1. Depiction of four examples of events that can lead to loss of normal ploidy while passing through mitosis (red frames). (1) Centrosome amplification giving rise to
more than two centrosomes induces multipolar spindles, leading to aneuploid cells; (2) a defect in separation of centrosomes triggers formation of a monopolar spindle and
abortive mitosis, leading to a tetraploid cell, just like a cytokinesis defect (3); and, finally, (4) improper kinetochore–microtubule attachment gives rise to aneuploid cells.

phase [6,7]. The kinase is then degraded by the protea-
some in a Cdh1-dependent manner [8,9]. During mitosis,
the protein also localizes to the poles of the mitotic spindle
(Box 1). Although these localizations are most commonly
observed, it seems that the centrosomal Aurora-A kinase
exchanges rapidly with an apparently large cytoplasmic
pool of Aurora-A [10].
The catalytic activity of Aurora-A kinase is closely
related to the activity of the mitotic centrosomes, which
participate in assembly of the bipolar spindle. The main
function of Aurora-A is to assist in the maturation of
duplicated centrosomes by recruiting proteins such as
D-TACC (Drosophila), g-tubulin, SPD-2 (C. elegans),
centrosomin and chTOG (MAP215-Msps-Zyg9) [10–14]
and consequently to participate in spindle assembly and
stability. Remarkably for a member of the protein kinase
family, Aurora-A needs to associate with some of its
substrate to be activated by autophosphorylation [15,16].
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Association with the substrate not only triggers autophos-
phorylation but also protects the kinase from dephos-
phorylation by a type 1 phosphatase that associates with
the kinase [17] (Figure 2). To date, TPX2 is the best-
understood protein that activates Aurora-A. TPX2 trans-
ports Aurora-A and activates it at the spindle poles
[15,16,18]. It should be noted that TPX2 is also an Aurora-A
substrate. A comparable mechanism has been described
in G2 phase, where the protein activating Aurora-A is
Ajuba [19]. Among the Aurora-A substrates are Eg5
(a kinesin-like protein involved centrosome separation
and spindle stability), CDC25B (a phosphatase activating
Cdk1–cyclinB), the tumor-suppressor p53 and BRCA-1
[20] [21–24]. Aurora-A functioning as a centrosome kinase
might also be involved in the asymmetric protein
localization during cell division that contributes to the
determination of cell fate [10]. However, the most unusual
function of the kinase was described by a laboratory
 Review TRENDS in Cell Biology Vol.15 No.5 May 2005 243

Box 1. The cell cycle and aurora kinases

The eukaryotic cell cycle is divided into four phases (Figure Ia): G1, S,
G2 and M (mitosis) that end with cytokinesis, during which two
daughter cells containing one centrosome and the original number of
chromosomes separate. Five sub-phases divide mitosis: prophase,
prometaphase, metaphase, anaphase and telophase. A crucial mitotic
event occurs in metaphase when the bipolar spindle assembles.
Faithful chromosome segregation indeed depends on chromosome
bi-orientation and alignment within this spindle. (b) Aurora kinases (in
red) have different localizations during mitosis. Aurora-A (on the top
panel) localizes on duplicated centrosomes from the end of S phase to
the beginning of the following G1 phase. The kinase spreads on the
spindle poles during metaphase until the end of anaphase and
remains at the centrosome in the beginning of G1, becoming
undetectable in mid-G1.
Both Aurora-B and overexpressed Aurora-C show the same
localization (on the bottom panel). Both kinases are chromosome
passenger proteins; they appear in the nucleus in prophase, localize to
kinetochores during prometaphase and metaphase and relocalize to
the equatorial spindle in anaphase and telophase. Finally, they localize
on the contractile ring on the midbody during cytokinesis.

(a) (b)
Metaphase Anaphase

se
ha

is
se

e
ap

se

es
se

as
ha

ha
et

in
Prometaphase

ha

ph
ap
om

ok
ap
op

lo
et

yt
2

An
Pr

Te
Pr

M
G

C
Telophase

Prophase
M Cytokinesis
Aurora-A

G2
Aurora-B or overexpressed Aurora-C

G1
S
TRENDS in Cell Biology

Figure I.

Type 1
phosphatase

Activator
Active Aurora
ATP P ATP
kinase

Inactive Aurora
kinase

Substrates
P
Phosphorylated
substrates
P
P
P ATP P

P
P

TRENDS in Cell Biology

Figure 2. Ways of regulating Aurora kinase. The Aurora kinase (blue) seems to continuously associate with a type 1 phosphatase (green) that keeps the activating threonine in
the T-loop in a dephosphorylated form. In the presence of an activator (pink) that could be a substrate, the phosphatase is pushed away and Aurora autophosphorylates (‘P’)
the activating threonine (or alternatively the activator). As long as the kinase remains bound to its activator, it can phosphorylate many other substrates (purple). Once the
activator leaves the kinase, the phosphatase dephosphorylates the activating threonine, and the kinase becomes inactive.

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244 Review TRENDS in Cell Biology Vol.15 No.5 May 2005

Intermediate complexes?

INCENP INCENP INCENP

P
P P P
Survivin Survivin Survivin Borealin

Aurora-B Aurora-B Aurora-B Aurora-B

P P P P

Complex # 1 Complex # 2

P
P
Survivin Borealin

Aurora-B

Speculative complex
TRENDS in Cell Biology

Figure 3. Aurora-B complexes. Aurora-B (red) forms different complexes in vivo. The kinase can be activated by the inner centromere protein INCENP that is also a substrate
(blue); this heterodimer has been found in vivo and could be responsible for the phosphorylation of histone H3 (complex #1). Survivin (brown) can also activate the kinase
in vitro, but it is not a substrate. Also Survivin–INCENP–Aurora-B complexes can form in vitro, but these might only be intermediate complexes. Indeed, a fourth protein
participates in the complexes in vivo – the protein Borealin – which is also an Aurora-B substrate but not an activator. This large complex could be involved in the spindle
checkpoint (complex #2). Finally, it seems that the large complex might contain another, as yet unidentified, protein (‘speculative complex’).

working on RNA translation controls: Aurora-A can phos-
phorylate CPEB (cytoplasmic polyadenylation element
binding protein), required for RNA polyadenylation and
translation during Xenopus oocyte maturation [25,26].
Aurora-B: the chromosome passenger kinase
The Aurora-B kinase belongs to the chromosome passenger
protein family (Box 1). Such proteins localize to the
kinetochores from prophase to metaphase and to the
central spindle and the midbody in cytokinesis [6].
Association of Aurora-B with the inner centromere protein
INCENP led to the conclusion that Aurora-B participates
in a ‘chromosome passenger complex’ [27,28]. In human
cells, INCENP is required to localize Aurora-B at the
kinetochores [27]. And, just like Aurora-A, Aurora-B
activation is triggered by autophosphorylation after asso-
ciation with its substrate INCENP (Figure 2) [29–31]. In
mammalian cells, Aurora-B is a component of a large
complex containing INCENP, survivin and Borealin that
forms a chromosome passenger complex [32,33]. Although
survivin is not an Aurora-B substrate, it associates with
the kinase and stimulates its activity [34–36]. Borealin,
however, is an Aurora-B substrate but not a kinase
activator. To summarize, Aurora-B seems to participate
in at least two different complexes: an Aurora-B–
INCENP–Survivin–Borealin complex and an Aurora-B–
INCENP complex (Figure 3).
So, what is the function of Aurora-B? Elimination of the
kinase by RNA interference clearly revealed that the
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kinase is required for cytokinesis [37–39]. But Aurora-B
fulfils at least three distinct related functions. Aurora-B is
a histone kinase, it is a spindle checkpoint kinase and a
cytokinesis kinase.
Aurora-B is indeed responsible for the mitotic phos-
phorylation of not only the celebrated Ser10 residue in the
tail of histone H3 [39–42] but also of Ser28 in H3 [43] and
of Ser7 in CENP-A [44]. These phosphorylation events are
thought to be necessary for chromosome condensation,
although the only direct evidence comes from Tetrahymena
[45]. It is quite likely, however, that these phosphorylations
might only initiate the recruitment of condensation and
segregation proteins on chromosomes [39,46].
Most interestingly, Aurora-B phosphorylates the micro-
tubule depolymerase MCAK (mitotic centromere-associ-
ated kinesin) [47]. This phosphorylation by aurora-B has
two effects: it inactivates the microtubule depolymerase
catalytic activity of MCAK and it targets MCAK to the
kinetochores [47–49]. The microtubule depolymerase
activity of MCAK can then be locally activated by a
phosphatase, presumably the human homolog of cdc14
[50] or some other MCAK activator, to correct any
incorrect kinetochore attachments to the spindle [47]. In
the absence of Aurora-B, MCAK does not localize to
kinetochores and incorrect attachments persist (Box 2).
During anaphase and telophase, Aurora-B phosphoryl-
ates Ser72 in vimentin, which is an intermediate filament
protein participating in formation of the cleavage furrow.
In the absence of Ser72 phosphorylation, the two daughter
 Review TRENDS in Cell Biology
Box 2. The metaphase–anaphase transition, checkpoint and spindle defects
During spindle assembly, sister chromatids remain linked by cohesins.
The sister chromatids of each individual duplicated chromosome
must then be attached by microtubules to centrosomes on opposite
sides of the spindle through their kinetochores. When this is achieved,
the spindle checkpoint is relieved, allowing destruction of the cohesins
and separation of the sister chromatids. The spindle checkpoint
inhibits the metaphase–anaphase transition until all kinetochores
have been attached to microtubules, establishing a correct level of
tension within the spindle.
The function of Aurora-B during bipolar spindle assembly is to
correct abnormal microtubule attachments to kinetochore pairs
(Figure Ia). In a normal situation, amphitelic attachment (3) of sister
kinetochores to opposite centrosomes leads to termination of the
(a)
Aurora-B Aurora-B
syntelic monotelic amphitelic merotelic
1 2 3 4
Metaphase
Spindle checkpoint ON Spindle checkpoint OFF
7 6
Anaphase
Figure I.
cells remain associated through long bridges of cyto-
plasm, and cytokinesis fails [51]. Aurora-B also phos-
phorylates MgcRacGAP, a GTPase-activating protein
(GAP) required for cytokinesis [52]. Phosphorylation of
Ser387 in MgcRacGAP occurs in the midbody and
activates its GAP activity towards RhoA. MgcRacGAP
and RhoA seem to regulate cortical movement during
cytokinesis [53]. The midbody localization of the kinesin-
like protein MKLP-1, whose function is required late in
cytokinesis, is also dependent on Aurora-B. Together,
these data clearly point to a central function for Aurora-B
during cytokinesis.
Aurora-C: only a male meiotic kinase or another
chromosome passenger protein?
The gene encoding Aurora-C was first isolated from a
testis cDNA library and the gene localized to Chr19q13
[54]. Northern blot analyses of Aurora-C then confirmed
that the kinase was indeed only detectable in testis
[55,56]. During spermatogenesis, high expression of
Aurora-C mRNA was detected mainly in pachytene
spermatocytes, concomitant with meiotic spindle for-
mation [57]. Although the protein level was not measured,
the data suggested that Aurora-C might be involved in
meiotic spindle formation [56]. Strikingly, western blot
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Vol.15 No.5 May 2005 245
spindle checkpoint and a normal anaphase (7). In the presence of
monotelic attachment (only one kinetochore linked to one pole) (2) or
syntelic attachment (both sister kinetochores to one pole) (1), the
spindle checkpoint remains on and separation of sister chromatids
cannot proceed. However, in the absence of Aurora-B, abnormal
merotelic attachments (one kinetochore to both centrosomes) (4) are
not detected by the checkpoint, anaphase proceeds (5) and can give
rise to aneuploidy (6). (b) Aurora-A is involved in centrosome
maturation and spindle assembly; in the absence of Aurora-A, many
spindle defects are observed: monopolar spindles with centrosomes
at the pole (1), multipolar spindles with centrosomes at each pole (2),
monoastral bipolar spindles with one pole lacking a centrosome (3),
and bipolar spindles with several centrosomes at one pole (4).
(b) (1) Monopolar (2) Multipolar
(3) Monoastral (4) Bipolar with several
bipolar centrosomes per pole
analysis performed by another group revealed that
Aurora-C was highly expressed in cancer cell lines such
as HepG2, HuH7, MDA-MB-453 and HeLa cells [55]. The
same study also reported the first Aurora-C localization
that was restricted to centrosomes from anaphase through
to cytokinesis [55]. However, the centrosome localization
of Aurora-C is not definitive, and others have never
observed this localization. Instead, Aurora-C has been
reported by Li et al. to be a chromosome passenger protein
strictly localizing in a manner similar to, or even with,
Aurora-B [58]. In their study, Aurora-C was actually found
to co-immunoprecipitate with Aurora-B [58]. It must be
noted, however, that the fidelity of the anti-pan-Aurora
antibodies used to reveal Aurora-B and -C that are
thought to recognize all three Aurora kinases might not
be trustworthy. However, interestingly enough, just as for
Aurora-B, Aurora-C is activated by INCENP, and over-
expression of INCENP together with Aurora-C leads to an
increased level of phosphorylation in vivo of histone H3, a
true Aurora-B substrate [58,59]. So can Aurora-C fulfil the
function of Aurora-B? A recent study has proved that
Aurora-C can rescue Aurora-B-depleted cells [59]. Never-
theless, one must bear in mind that, to date, Aurora-C has
not been found expressed in somatic cells, and its
expression is restricted to testis.
246 Review TRENDS in Cell Biology Vol.15 No.5 May 2005

Aurora kinases control cell ploidy and centrosome

number Aurora-A Aurora-B
Surviving without Aurora kinase defect defect
Cells usually do not tolerate a lack of Aurora kinase. In the
absence of Aurora-A, centrosomes fail to assemble bipolar G2
spindles, inducing the formation of several abnormal
mitotic spindles such as spindles with short astral Prolonged mitosis: Normal mitosis
several hours Length: one hour
microtubules, monopolar spindles (one pole), monoastral
MITOSIS
bipolar spindles (bipolar, but with one pole lacking a
centrosome), bipolar spindles with multiple centrosomes
at the poles, and multipolar spindles (Box 2) [11,60]. A
decrease in Aurora-A protein level induced by RNA
interference leads to G2–M arrest, many spindle defects,
the appearance of tetraploid cells and apoptosis [61].
Tetraploid cells are formed because mitosis aborts and
cells enter the following G1 with not one but two nuclei p53–/– p53+/+ p53+/+
and two centrosomes. It is indeed well known that cells
escape mitosis when it persists too long; for example this
has been observed in the presence of spindle poisons [62].
In the following G1 phase, cell-cycle progression is G1
arrest
arrested by a so-called ‘post-mitotic checkpoint’ [63].
Whether this is a ‘tetraploid checkpoint’ is debatable
[64–66]. This G1 arrest following abortive mitosis owing to S phase S phase Cell death S phase
a spindle defect in the previous mitosis is a real curiosity.
1 2 3 4
Although the G1-activated checkpoint seems to be a
classic one, depending on p53 and the retinoblastoma
protein pRb [62], it is unknown what is detected in G1 that
Mitosis with multipolar spindles
triggers the cell-cycle arrest (Figure 4). However, the G1
checkpoint is required for the cell to trigger apoptosis.
The cells better tolerate the absence of Aurora-B than 5 6 7
Aurora-A. Inhibition of Aurora-B provokes two main events: S phase Cell death S phase
first, it eliminates the mitotic checkpoint because cells
without Aurora-B activity do not arrest in mitosis in the TRENDS in Cell Biology
presence of nocodazole and, second, it efficiently inhibits
Figure 4. Consequences of defects in Aurora kinases. In the presence of defective
cytokinesis [67]. The cells do not divide and instead become Aurora-A (top left), mitosis is prolonged because the presence of an abnormal
tetraploid, with two centrosomes. In this case, apoptosis is spindle maintains the mitotic checkpoint on. But the cell will eventually escape from
not observed (Figure 4). Elimination of Aurora-C through mitosis and become tetraploid. In cells containing inactive p53, tetraploid cells will
readily enter S phase (1). In cells containing wild-type p53, tetraploid cells arrest in
RNA interference in immortalized cells such as HeLa also the subsequent G1 phase and, depending on the severity of the defects detected by
leads to multinucleated cells, just as for Aurora-B. Further- the post-mitotic (G1) checkpoint, they will either enter S phase (2) or die (3). In the
more, double knockdown of Aurora-B and Aurora-C shows presence of defective Aurora-B (top right), the length of mitosis is not changed
because the spindle checkpoint is now deficient. However, cytokinesis does not
additive effects, indicating that both kinases might share occur and the cell becomes tetraploid. The G1 post-mitotic checkpoint is not
the same functions during mitosis [59]. activated because mitosis has not been prolonged, and the cell enters S phase (4).
There is a major difference between tetraploid cells The tetraploid cells in the above cases are not equivalent: without Aurora-A, they
will survive in p53-defective cells (5) and die in cells possessing wild-type p53 (6),
obtained after Aurora-A elimination and after Aurora-B or whereas, without Aurora-B, the cells will keep dividing (7).
Aurora-C elimination. First, without Aurora-A, the mito-
tic checkpoint detects the spindle defects, arrests the cells
in mitosis, from which they eventually escape a few hours they might be comparable to tetraploid cells that survive
later. But these tetraploid cells then face a second after limited Aurora-A depletion.
checkpoint in G1, which depends on p53. These cells can Clearly, the act of entering mitosis for a tetraploid cell is
follow two routes: they arrest in G1 and die or they enter S another challenge, it is not the amount of DNA that
phase and progress through the cell cycle. This choice matters – rather, it is the number of centrosomes. A
might depend on how badly the previous mitosis has been tetraploid G1 cell contains two centrosomes that will
affected. After serious defects and a long mitotic arrest, duplicate during the following S phase, driving a cell
tetraploid cells die, whereas, after mild defects and a short containing four centrosomes into mitosis. Usually, such a
period of arrest, tetraploid cells survive and go through cell will give rise to multipolar spindles when entering
another cycle. But again, what triggers this G1 checkpoint mitosis. This is true for tetraploid cells obtained after
remains a central question. Second, tetraploid cells inhibition of any Aurora kinase. However, again it will
generated by a lack of Aurora-B (and possibly the same then take more time for the checkpoint to be switched off
for Aurora-C) do not have to face this G1 checkpoint and and for the cell to exit mitosis in cells lacking aurora-A. By
do not die; presumably, because the mitotic checkpoint has contrast, cells lacking Aurora-B will exit from mitosis on
not been activated, mitosis is not delayed. In some ways, schedule because of the lack of checkpoint activation.
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 Review TRENDS in Cell Biology
Again, the G1 checkpoint will take care of cells that have
had a prolonged mitosis by inducing G1 phase cell-cycle
arrest and cell death.
Two much aurora causes problems too
Now for the most intriguing part of the story. Not only does
overexpression of any of the aurora kinases lead to
polyploid cells containing multiple centrosomes, but also
the activity of the kinase itself is dispensable. In the case
of Aurora-A, both the active and the inactive kinase gave
rise to multinucleated cells containing multiple centro-
somes with equal efficiency in HeLa cells [68]. However, in
primary mouse embryonic fibroblasts, Aurora-A activity
seemed essential for induction of polyploidy [69]. This
might be explained by inactivation of p53 through
phosphorylation of serines 215 and 315 by Aurora-A
[22,23]. Phosphorylation of Ser215 inactivates p53 trans-
activation activity, whereas phosphorylation of Ser315
triggers p53 degradation. Not only does Aurora-A over-
expression lead to abnormal mitosis but it provides a way
to escape the p53-dependent G1 post-mitotic checkpoint.
This is in agreement with the fact that only the active
Aurora-A can induce polyploidy in primary cells [69].
Overexpression of inactive Aurora-A induces abnormal
spindles, leading to prolonged mitosis, G1 checkpoint
arrest and cell death. By contrast, overexpression of active
Aurora also induces an abnormal spindle that leads to
prolonged mitosis, but the cells survive because active
Aurora-A inactivates p53 and promotes its degradation.
There are also differences between active Aurora-B
or -C and inactive versions of the protein. The inactive
kinase is more efficient at inducing polyploidy [30,59,70].
The fact that too much active or too much inactive kinase
can give rise to the same phenotype might also suggest
that the overexpressed kinase has a dominant-negative
effect or that Aurora kinases contribute to protein
complexes. Increasing the level of the kinase disrupts
the stoichiometry of the protein–protein interactions,
inhibiting the formation of active protein complexes.
Furthermore, the phenotype obtained after overexpression
of Aurora-A or Aurora-B is enhanced in p53K/K cells [68].
This again is indicative of a central role of a p53-dependent
checkpoint in the following G1 phase to establish polyploidy.
To be or not to be an oncogene – that is the question
The protein encoded by the Aurora-A gene was first named
BTAK for ‘breast tumor activated kinase’ because its gene,
located at 20q13, was found amplified and its mRNA
overexpressed in breast tumors. The presence of the
amplicon 20q13 in breast tumors is an indicator of poor
prognosis [71]. But a breakthrough came from two
different groups that demonstrated that ectopic over-
expression of Aurora-A was sufficient to transform
NIH3T3 and rat1 cells and that transformed cells induced
tumors when implanted in nude mice [72,73]. Since 1998,
Aurora-A has been designated as an oncogene, and
approximately 30 published studies have reported over-
expression of Aurora-A in many types of tumors. However,
overexpression of Aurora-A in primary MEF cells does
not induce colony formation, clearly indicating that
Aurora-A overexpression alone is insufficient to induce
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Vol.15 No.5 May 2005 247
carcinogenesis [69]. The same authors also indicated that
they could not obtain any colony formation when Aurora-A
was overexpressed together with a trans-dominant p53
gene that eliminates the DNA damage checkpoint or
together with BCL-2 that eliminates an apoptosis path-
way. As immortalized NIH3T3 and rat1 cells carry many
genetic abnormalities, it must be assumed that other
defects cooperate with Aurora-A to induce oncogenicity.
Identification of the responsible genes is now a priority.
This situation has also been confirmed in vivo. A trans-
genic mouse designed to overexpress Aurora-A in an
inducible manner in mammary glands does not develop
any tumors – only formation of tetraploid cells and
apoptosis are observed in the mammary epithelium [74].
The mouse model can now be used to search the genetic
background required to get an oncogene effect from
overexpression of Aurora-A.
Aurora-A was also recently identified as a candidate
low-penetrance tumor-susceptibility gene. A T-to-A poly-
morphism resulting in a change in phenylalanine 31 (F31)
to isoleucine (I31) has been observed in the aurora-A gene
and reported to be associated with the degree of aneu-
ploidy in human colon tumors [75]. The F31I variant is
also preferentially amplified in esophageal squamous cell
carcinomas, and this correlates with an increase in
aneuploidy [76]. However, whether the presence of this
polymorphism correlates with the risk of breast cancer
remains debatable. Indeed, a report indicates that homo-
zygotes for the F31I mutation have increased suscepti-
bility to breast carcinoma [77], whereas another indicates
no correlation [78].
In the case of Aurora-B, the situation is unclear. The
kinase is overexpressed in cancer cells, and an increased
level of Aurora-B correlates with advanced stages of
colorectal cancer [79–82]. Only one report strongly
suggests a direct link between Aurora-B and carcino-
genesis [83]. Stable clones overexpressing Aurora-B have
been isolated and injected in nude mice. The authors used
CHE diploid fibroblasts carrying a G245S mutation in
both alleles of p53 because they could not isolate any
stable clone using wild-type CHE. The mutation in p53
eliminates transactivation of p21, and consequently
abrogates the p53-dependent G1 checkpoint. More impor-
tantly, nontransfected cells induce tumor formation when
injected in nude mice, but these tumors do not induce any
metastases. However, mice injected with p53(G245S) cells
overexpressing Aurora-B form more aggressive tumors
that do develop metastases [83]. It was suggested that
Aurora-B overexpression might be a secondary event in
p53-defective tumor cells that leads to malignancy [83]. In
both Aurora-A- and Aurora-B-overexpressing cells,
defects in p53 seem to play an essential role in stabilizing
polyploidy.
Which one of the aurora kinases is the best anti-cancer
therapeutic target?
It has been established that, first, overexpression of
Aurora-A can transform cells carrying genetic defects
and, second, that Aurora-B overexpression induces tumor
metastasis. In both cases, the catalytic activity of the
kinase is required. So would it be a good idea to develop
248 Review TRENDS in Cell Biology
inhibitors of Aurora as chemotherapeutic drugs? It is
always difficult to answer such questions when the
functions of the kinases are not yet fully understood. But
usually one takes a chance – and indeed a breakthrough
was announced recently. A compound named VX-680 that
inhibits all three Aurora kinases is reported to possess an
antiproliferative effect and to induce tumor regression in
animal models, indicating that drugs targeting Aurora
have an excellent potential for clinical trials [84,85]. But
there is an apparent paradox – although only Aurora-A is
considered an oncoprotein, it seems that it is Aurora-B
inhibition that induces tumor regression. Indeed, inhibi-
tors of Aurora kill proliferating cells through apoptosis
after accumulation of tetraploid cells generated by
inhibition of cytokinesis and blocking mitotic histone H3
phosphorylation [84]. This undoubtedly corresponds to the
phenotype obtained only after RNA interference against
Aurora-B and not against Aurora-A. This result was
shocking because everybody had been looking for an
inhibitor specific for Aurora-A. However, there might be
an explanation. Inhibition of Aurora-A leads to abnormal
spindles that can be observed only in cells having a
functional spindle checkpoint. However, in the presence of
an anti-Aurora compound that inhibits Aurora-A and
Aurora-B, the abnormal spindles arising from the lack of
Aurora-A activity might not be visible because, in the
absence of Aurora-B activity, they would not trigger
mitotic arrest. Mitosis will progress with formation of an
abnormal spindle until cytokinesis that itself will abort in
the absence of Aurora-B activity (no cytokinesis), leading
to a phenotype that looks like the one observed after
Aurora-B RNA interference. So possibly the best anti-
tumor drug will have to inhibit all the Aurora kinases.
Several other inhibitors have been developed against
Aurora kinases. Some inhibitors are currently in pre-
clinical development such as the compounds from Astra-
Zeneca AZD1152 (http://www.astrazeneca.ch/corp/corp-
archiv/corp-archiv-read.htm?idZ17180) and compound
677 [86], both described as inhibitors of Aurora-B.
Academic research laboratories are analysing Aurora
functions using other compounds – for example, Hesper-
adin, which inhibits Aurora-B and several other kinases
[67], and ZM447439, which inhibits both Aurora-A and
Aurora-B [87]. It is likely that many pharmaceutical
companies are now searching for inhibitors of the Aurora
proteins.
Concluding remarks
The similarities and differences between the three Aurora
kinases seem to fit with the proposed evolutionary origin
of the kinases [88]. Aurora kinases evolved from a common
chordate ancestor, then two Aurora kinases appeared
in cold-blooded vertebrates: a true Aurora-A kinase and
an Aurora-B/C ancestor. In mammals, the Aurora-B/C
ancestor gave rise to two closely related kinases – Aurora-B
and Aurora-C. It is not surprising that these last two
kinases colocalize (to kinetochore and midbody) and share
substrates (histone H3). Overexpression of the three
kinases has been observed in a large variety of tumors
containing polyploid cells with an abnormal number of
centrosomes. So, where is the link? Is there any evidence
www.sciencedirect.com
Vol.15 No.5 May 2005
that overexpression of Aurora kinases leads to polyploidy
and abnormal centrosome number? The answer is yes.
Does overexpression of Aurora kinase underlie the origin
of chromosome instability? The answer is yes too. Is this
how Aurora overexpression contributes to carcinogenesis?
The answer is clearly no. Indeed, overexpression of active
and inactive Aurora gives rise to chromosome instability
through the formation of polyploid cells containing
abnormal centrosome numbers [59,68]. However, only
active kinases, at least for Aurora-A and Aurora-B,
respectively, transform cells or induce metastasis. This is
an extremely important point because, if overexpression of
the active kinase or inactive kinase gives rise to the same
phenotype, it is clear that the kinase activity participates
in carcinogenesis by phosphorylating proteins not
involved in the appearance of the phenotype. This has
recently been confirmed in a report showing that Aurora-A
overexpression potentiates the oncogene activity of HRAS,
not by interfering with the ploidy of the cell or the number
of centrosomes but by influencing cell growth [89]. Also
Aurora-A phosphorylation of p53, leading to the inhibition
of its transactivation activity and to its degradation, might
be a pivotal point. The exact role of Aurora-A in
carcinogenesis and Aurora-B in metastasis remains a
mystery; however, some indications point towards control
of a G1 phase post-mitotic checkpoint. But even if we
know that a p53 defect plays a central role in allowing
tetraploid cells to enter S phase following an abnormal
mitosis, we still do not know what exactly is triggering this
p53-dependent checkpoint. Understanding this mechan-
ism seems crucial. Furthermore, future investigations
must concentrate on the identification of the genetic
defects that contribute to making Aurora-A an oncogene.
Identifying other substrates of Aurora kinases will also
undoubtedly help.
In conclusion, let’s think about how the science might
actually progress. We might soon be able to use an
inhibitor of Aurora kinase to treat cancers, without
knowing exactly the function of Aurora kinases, without
knowing how Aurora kinases contribute to carcinogenesis
and without knowing why the Aurora inhibitors kill the
tumors.
Acknowledgements
I express my apologies to all the authors who have published work related
to this review but have not been cited here owing to space constraints.
Research in the Claude Prigent laboratory is financed by the Ligue
Nationale Contre le Cancer (équipe labellisée) and by the CNRS. Clotilde
Petretti is a fellow of the region Bretagne.
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