Vader, G., Medema, R. H. & Lens, S. M. The chromosomal passenger complex: guiding Aurora-B through mitosis. J. Cell Biol. 173, 833-837

Article (PDF Available)inThe Journal of Cell Biology 173(6):833-7 · July 2006with38 Reads
Impact Factor: 9.83 · DOI: 10.1083/jcb.200604032 · Source: PubMed
During mitosis, the chromosomal passenger complex (CPC) orchestrates highly different processes, such as chromosome alignment, histone modification, and cytokinesis. Proper and timely localization of this complex is the key to precise control over the enzymatic core of the CPC, the Aurora-B kinase. We discuss the molecular mechanisms by which the CPC members direct the dynamic localization of the complex throughout cell division. Also, we summarize posttranslational modifications that occur on the CPC and discuss their roles in regulating localization and function of this mitotic complex.

Full-text (PDF)

Available from: René H Medema
© The Rockefeller University Press $8.00
The Journal of Cell Biology, Vol. 173, No. 6, June 19, 2006 833–837
JCB 833
The chromosomal passenger complex (CPC) has recently
received much attention as an important mitotic regulatory
complex. In early mitosis, this complex promotes chromosome
alignment by correcting misattachments between chromosomes
and microtubules of the mitotic spindle (Carmena and Earnshaw,
2003). Additionally, the CPC is responsible for the dis placement
of heterochromatin protein-1 (HP-1) from mitotic chromosomes
by modifying Histone H3 (Fischle et al., 2005; Hirota et al.,
2005). At the end of mitosis, the CPC regulates the proper
execution of cytokinesis (Carmena and Earnshaw, 2003). All
these functions can be attributed to the action of the enzymatic
heart of the CPC, the Aurora-B serine/threonine protein kinase,
as chemical inhibition of this kinase impairs all CPC functions
described above (Ditch eld et al., 2003; Hauf et al., 2003;
Fischle et al., 2005; Hirota et al., 2005). Here, instead of focus-
ing on the speci c functions of the CPC during mitosis, we
primarily discuss how the nonenzymatic components of the
CPC enable Aurora-B to function properly during mitosis.
The CPC can be regarded as a complex similar to the cyclin/
CDK kinase complexes, in which the binding of a nonenzymatic
protein to its enzymatic partner is essential for functioning of
the kinase. Instead of one nonenzymatic/regulatory subunit in
a cyclin/CDK complex, the CPC contains three nonenzymatic
subunits, all of which are essential for the function of Aurora-B.
These subunits determine activity, localization, stability, and
possibly also substrate speci city of Aurora-B. In human
cells, these subunits are Survivin, the inner centromere protein
(INCENP), and Borealin/Dasra-B (hereafter referred to as
Borealin; Fig. 1). These proteins are conserved among species,
as in all investigated model organisms similar proteins have been
identi ed. Borealin forms an exception, because orthologues
have not been identi ed so far in Saccharomyces cerevisiae
and Schizosaccharomyces pombe. Also, the putative functional
orthologue of Borealin in Caenorhabditis elegans, CSC-1, is
only distantly related to other Borealin proteins (Gassmann et al.,
2004). Interestingly, Bir1p, the yeast homologue of Survivin,
is much larger than its mammalian orthologues, raising the
intriguing possibility that Survivin and Borealin are combined in
a single protein in yeast and that Bir1p has diverged into different
polypeptides during evolution. In all studied organisms, the CPC
proteins function in multiprotein complexes, and in mammalian
cells, complex formation between the CPC proteins is needed
for protein stability (Honda et al., 2003; Vader et al., 2006).
Recent evidence suggests that two distinct passenger complexes
exist during mitosis: one containing all four CPC members and
another consisting of INCENP and Aurora-B (Gassmann et al.,
2004). Of these two complexes, the quaternary CPC functions
during chromosome alignment and cytokinesis, whereas the
INCENP–Aurora-B complex might be responsible for modifying
Histone H3 (Gassmann et al., 2004).
How do these proteins dictate Aurora-B function? The
CPC proteins show a very dynamic localization during mitosis
that gave them their name (Earnshaw and Bernat, 1991): they
initially paint the entire chromatin during the onset of mitosis,
move from the chromosome arms toward the inner centromeric
chromatin (in between the kinetochores, the sites of microtubule
attachment) during prometaphase, relocalize to the microtubules
of the central spindle at the metaphase–anaphase transition, and
nally concentrate at the midbody during telophase/cytokinesis.
This localization correlates with the diverse functions of the
CPC during mitosis: modifying histones at the chromatin, cor-
recting misattachments while at the centromere, and regulating
cytokinesis at the central spindle (and later midbody). Given the
correlation between localization and function, it is apparent that
timely and proper localization of the CPC is the key to allowing
Aurora-B to exert its diverse functions during mitosis.
The chromosomal passenger complex: guiding
Aurora-B through mitosis
Gerben Vader, René H. Medema, and Susanne M.A. Lens
Department of Medical Oncology, University Medical Center, 3584 CG Utrecht, Netherlands
During mitosis, the chromosomal passenger complex
(CPC) orchestrates highly different processes, such as chro-
mosome alignment, histone modifi cation, and cytokinesis.
Proper and timely localization of this complex is the key to
precise control over the enzymatic core of the CPC, the
Aurora-B kinase. We discuss the molecular mechanisms
by which the CPC members direct the dynamic localization
of the complex throughout cell division. Also, we summarize
posttranslational modifi cations that occur on the CPC and
discuss their roles in regulating localization and function
of this mitotic complex.
Correspondence to Susanne M.A. Lens:
Abbreviations used in this paper: BIR, baculovirus IAP repeat; CPC, chromo-
somal passenger complex; INCENP, inner centromere protein.
Page 1
JCB VOLUME 173 NUMBER 6 2006 834
Regulation of Aurora-B localization
by the CPC proteins
To allow timely CPC localization, one or multiple CPC sub-
units should recognize a docking site (i.e., receptor) on chro-
mosome arms, centromere, or central spindle. Because of the
molecular differences between these structures (e.g., centro-
meric chromatin versus microtubules on the central spindle), it
is likely that different receptors exist on these structures and
that different CPC members are involved in the speci c target-
ing of Aurora-B. The mechanism by which the CPC is targeted
to the chromosome arms in unclear, but a plausible possibility
would be via interaction with HP-1, as INCENP has been
described to interact with this chromatin-associated protein
(Ainsztein et al., 1998). HP-1 displacement from chromosome
arms is mediated by Aurora-B (Fischle et al., 2005; Hirota et al.,
2005), which could explain the transient localization of the
CPC at chromosome arms during prometaphase. Also, the CPC
receptors at the centromeres are unknown, but there are clues to
the mechanisms by which the CPC interacts with its centro-
meric receptors (Fig. 2). INCENP-deletion studies identi ed an
-terminal domain needed for centromere localization of the
CPC (Ainsztein et al., 1998). Survivin interacts with INCENP
via this domain, and replacement of this domain with Survivin
suf ces for targeting a functional CPC to the centromeres (Vader
et al., 2006). When Survivin is linked covalently to INCENP,
a functional CPC can be targeted, albeit less ef ciently, to
the centromeres and central spindle in the absence of Borealin
(Vader et al., 2006). Thus, Borealin appears to play only a minor
role in centromere targeting when Survivin and INCENP are
forced into a complex. However, Borealin is essential for cen-
tromere localization of the endogenous proteins, suggesting it
plays a major role in promoting interaction between Survivin
and INCENP. Indeed, depletion of Borealin disrupts the inter-
action between exogenously expressed Survivin and INCENP
(Vader et al., 2006). Similarly, ef cient in vitro interaction be-
tween C. elegans Survivin (BIR [baculovirus IAP repeat] 1) and
INCENP (ICP-1) depends on the Borealin orthologue CSC-1
(Romano et al., 2003). Interestingly, recent data showed that
Borealin also interacts with the NH
terminus of INCENP and
that Borealin can interact with double-stranded DNA in vitro
(Klein et al., 2006), suggesting that, in addition to facilitating
the Survivin–INCENP interaction, the contribution of Borealin
to centromere targeting is mediated via direct interaction with
chromatin (Klein et al., 2006). Collectively, this allows for a
model in which Survivin and Borealin cooperatively mediate
centromere targeting of the CPC through multiple docking sites,
including the chromatin itself. By interacting with the NH
terminus of INCENP, these proteins can then recruit INCENP and
Aurora-B to centromeres. Because Survivin and Borealin can
oligomerize in vitro (Chantalat et al., 2000; Muchmore et al.,
2000; Verdecia et al., 2000; Gassmann et al., 2004), it is possible
that a heterooligomer of Borealin and Survivin assembled on
the NH
terminus of INCENP forms the centromere binding
interface of the CPC. Within Survivin, the BIR domain is the
most likely domain to interact with putative CPC receptors
at the centromere, as disruption of this domain impaired CPC
centromere function (but not Borealin interaction; Lens et al.,
2006). Interestingly, Bir1p, the S. cerevisiae Survivin ortho logue,
interacts with Ndc10, a subunit of the centromere binding
factor-3 complex (Yoon and Carbon, 1999), making this protein
a good candidate for a CPC centromere receptor. However,
a mammalian orthologue of Ndc10 has not been identi ed.
Clearly, identifying Survivin (BIR domain) and Borealin inter-
actors is necessary to further elucidate the mechanisms of CPC
centromere targeting.
Most of our knowledge regarding CPC centromere target-
ing is based on immuno uorescence data in  xed cells. How-
ever, it is clear that association of the CPC to centromeres is
Figure 1. Interactions within the CPC. Schematic representation of direct
interactions between CPC proteins and phosphorylations of Aurora-B
within the CPC. Survivin and Borealin interact with the NH
terminus of
INCENP, whereas Aurora-B binds the COOH-terminal IN-box in INCENP.
Mapped Aurora-B phosphorylation sites are indicated.
Figure 2. Targeting mechanisms of the CPC. For chromatin localization
during prometaphase, interaction between HP-1 and INCENP might be
required. A multimeric complex of Survivin and Borealin might coopera-
tively serve as binding interface at the centromere. Within Survivin, the
BIR domain is important for centromere targeting, whereas the COOH
terminus (C) plays a role in central spindle localization. Putative centro-
mere receptors are Ndc10 and centromeric DNA. At the central spindle
during anaphase, Aurora-B interacts with Mklp2 and INCENP has an
affi nity for microtubules (MTs) regulated by Cdc14. Survivin can also
interact with microtubules, but it is unknown whether this contributes to
central spindle targeting.
Page 2
highly dynamic. For example, Survivin localizes dynamically
to the centromere (Beardmore et al., 2004). Inhibition of Aurora-B
or depolymerization of microtubules greatly reduces Survivin
turnover at centromeres (Beardmore et al., 2004), suggesting
that CPC localization and microtubule attachment are linked
during prometaphase/metaphase. Indeed, recent evidence showed
that proper dynamics of Survivin (and presumably the entire
CPC) at the centromeres is essential for proper chromosome
alignment. Vong et al. (2005) identi ed ubiquitination as a
posttranslational modi cation required for proper targeting and
dynamics of Survivin at centromeres. Interference with this
process, by removing either a deubiquitinating enzyme (hFAM)
or a ubiquitin binding protein (Ufd1) impaired localization and
turnover of Survivin at the centromeres and, as a consequence,
disturbed chromosome alignment (Vong et al., 2005). More-
over, Survivin is also an Aurora-B substrate, and mimicking
constitutive phosphorylation impairs centromere localization
(Wheatley et al., 2004). It will be interesting to see whether
these modi cations are interdependent and/or in uence each
other and how posttranslational modi cations on Survivin can
in uence the function of the entire CPC.
From centromere to central spindle
To function during cytokinesis, Aurora-B needs to translocate
from the centromeres to the central spindle at the metaphase–
anaphase transition. In S. cerevisiae, this translocation is nega-
tively regulated by cyclin B/Cdk1–dependent phosphorylation
of INCENP. Dephosphorylation of residues within the coiled-
coil domain of INCENP by Cdc14 triggers translocation of the
CPC to the central spindle (Pereira and Schiebel, 2003). How-
ever, a recent phosphoproteomics analysis failed to identify
phoshosites in the coiled-coil domain of human INCENP. Yet,
multiple putative cyclin B/Cdk1 phosphosites were identi ed
in a region in INCENP previously shown to interact with HP-1
(Ainsztein et al., 1998; Nousiainen et al., 2006). Together with
the observation that expression of a nondegradable cyclin B
mutant prevented spindle transfer of Aurora-B during anaphase
in human cells (Murata-Hori et al., 2002), this suggests that
phospho-dependent regulation of CPC spindle transfer is con-
served but that different domains in INCENP might be involved.
Besides the phosphosites found within the HP-1 binding do-
main, several additional residues in INCENP were found to be
phosphorylated during mitosis, suggesting complex phospho-
dependent regulation of the human CPC (Nousiainen et al.,
2006). Relocalization of the CPC from centromeres to the cen-
tral spindle at the metaphase–anaphase transition also requires
dynamic microtubules, as treatment of anaphase cells with the
microtubule-stabilizing drug taxol impaired central spindle tar-
geting (Wheatley et al., 2001). INCENP interacts directly with
polymerized microtubules via its coiled-coil domain (Mackay
et al., 1993). Additionally, a small domain in the NH
of INCENP interacts with β-tubulin and is essential for ef cient
spindle localization of the CPC (Ainsztein et al., 1998; Wheatley
et al., 2001). Survivin can also interact in vitro with polymer-
ized microtubules, and mutation of the coiled-coil domain in
Survivin impaired this interaction (Li et al., 1998), suggesting a
dual interaction of the CPC with microtubules (i.e., via INCENP
and Survivin). However, it is unclear whether this interaction is
crucial for proper CPC localization during anaphase. Besides
microtubules, central spindle localization of the CPC also de-
pends on Mklp2, a mitotic kinesin. In human cells depleted of
Mklp2, the CPC fails to relocalize to the central spindle during
anaphase (Gruneberg et al., 2004). Aurora-B directly interacts
with Mklp2 in human cells (Gruneberg et al., 2004), and simi-
larly, C. elegans Aurora-B functionally interacts with the related
kinesin Zen-4 (Severson et al., 2000). In this case, Aurora-B
itself targets the CPC to the central spindle by interacting with
Mklp2. Additionally, Mklp2 interacts with and is required for
central spindle localization of human Cdc14a, a homologue of
S. cerevisiae Cdc14. Altogether, relocalization of the CPC to the
central spindle depends on the orchestrated actions of at least
spindle microtubules, Mklp2, and Cdc14 (Fig. 2).
Is centromere localization a prerequisite for central spin-
dle localization? Initial experiments in which disruption of cen-
tromeric localization also impaired anaphase spindle transfer
indicated that it might be (Ainsztein et al., 1998). However,
Drosophila melanogaster mutants undergoing meiosis without
chromosomes can execute cytokinesis and concomitantly local-
ize Aurora-B to the central spindle (Bucciarelli et al., 2003).
Additionally, recent experiments revealed that the COOH-
terminal region of Survivin (the region containing the coiled-
coil domain that binds microtubules in vitro [Li et al., 1998]) is
suf cient to direct a functional CPC to the central spindle without
prior centromere concentration (Lens et al., 2006). It will be
interesting to investigate whether this domain in Survivin inter-
acts in vivo with one of the known central spindle CPC receptors
or with as-yet-unidenti ed central spindle receptors. Taken as a
whole, it seems that, although in normal cells centromeric and
central spindle localization are tightly linked, they can be un-
coupled and involve different targeting mechanisms.
Activation of Aurora-B
and CPC phosphorylation
In vitro experiments have demonstrated that INCENP is criti-
cally needed to activate Aurora-B. INCENP interacts with
Aurora-B via its conserved COOH-terminal IN-box, and incubation
of this domain with Aurora-B causes an increase in kinase
activity (Kang et al., 2001; Bolton et al., 2002). Addition of
Borealin does not activate Aurora-B in vitro (Gassmann et al.,
2004), whereas con icting data exist regarding the ability of
Survivin to activate Aurora-B. In Xenopus laevis extracts, Sur-
vivin is needed for full Aurora-B activity (Bolton et al., 2002),
but in vitro experiments with human proteins did not reveal
a role for Survivin in activating Aurora-B, whereas INCENP
could activate Aurora-B in this in vitro setup, suggesting that
INCENP is the major Aurora-B activator in human cells (Honda
et al., 2003). Alternatively, in vivo regulatory mechanisms
might exist (e.g., additional proteins and/or posttranslational
modi cations) that are needed for additional Survivin-dependent
activation of Aurora-B.
INCENP, Survivin, and Borealin are subject to phos-
phorylation by Aurora-B (Fig. 1). INCENP phosphorylation
at a TSS motif close to the IN-box induces a conformational
change in Aurora-B, causing full activation of Aurora-B
Page 3
JCB VOLUME 173 NUMBER 6 2006 836
(Sessa et al., 2005). This phosphorylation is essential for
in vitro (Honda et al., 2003; Sessa et al., 2005) and in vivo
(unpublished data) functionality of Aurora-B. Survivin is phos-
phorylated on threonine-117 by Aurora-B in vitro (Wheatley
et al., 2004), and this phosphorylation is involved in regulating
localization (see Regulation of Aurora-B localization by the
CPC proteins). The COOH terminus of Borealin is phosphory-
lated by Aurora-B, but the functionality of this phosphorylation
is unknown (Gassmann et al., 2004). Further research regarding
these phosphorylations in CPC function (e.g., on localization
and dynamics) will be necessary to deepen our understanding
of CPC regulation. Additionally, it will also be interesting to
explore whether INCENP, Survivin, and Borealin also in uence
substrate speci city and recognition of Aurora-B.
Concluding remarks
Aurora-B kinase activity is essential for faithful chromosome
segregation and execution of cytokinesis. To ful ll these criti-
cal functions, the kinase needs to be in its active conformation
at the right place at the right time. It is clear that activity and
localization of Aurora-B is tightly controlled by its interaction
partners INCENP, Survivin, and Borealin. Because Aurora-B is
targeted to different structures during prometaphase/metaphase
and anaphase (i.e., centromeric chromatin and microtubules/
tubulin, respectively), it will be a challenge to build a complete
picture of the CPC-speci c receptors on these structures and
the composition of CPC proteins that serve as ligands for these
receptors. Because Aurora-B is a promising anti-cancer drug
target (Keen and Taylor, 2004), interference with these receptor–
ligand interactions by small molecules could be an alternative
therapeutic strategy for disturbing Aurora-B function.
We thank Dr. M. van Vugt for comments on the manuscript.
Our work is supported by the Dutch Cancer Society (NKI 2002-2764).
Submitted: 6 April 2006
Accepted: 11 May 2006
Ainsztein, A.M., S.E. Kandels-Lewis, A.M. Mackay, and W.C. Earnshaw. 1998.
INCENP centromere and spindle targeting: identi cation of essential
conserved motifs and involvement of heterochromatin protein HP1.
J. Cell Biol. 143:1763–1774.
Beardmore, V.A., L.J. Ahonen, G.J. Gorbsky, and M.J. Kallio. 2004. Survivin
dynamics increases at centromeres during G2/M phase transition and is
regulated by microtubule-attachment and Aurora B kinase activity. J. Cell
Sci. 117:4033–4042.
Bolton, M.A., W. Lan, S.E. Powers, M.L. McCleland, J. Kuang, and P.T.
Stukenberg. 2002. Aurora B kinase exists in a complex with survivin and
INCENP and its kinase activity is stimulated by survivin binding and
phosphorylation. Mol. Biol. Cell. 13:3064–3077.
Bucciarelli, E., M.G. Giansanti, S. Bonaccorsi, and M. Gatti. 2003. Spindle as-
sembly and cytokinesis in the absence of chromosomes during Drosophila
male meiosis. J. Cell Biol. 160:993–999.
Carmena, M., and W.C. Earnshaw. 2003. The cellular geography of aurora
kinases. Nat. Rev. Mol. Cell Biol. 4:842–854.
Chantalat, L., D.A. Skou as, J.P. Kleman, B. Jung, O. Dideberg, and R.L.
Margolis. 2000. Crystal structure of human survivin reveals a bow tie-
shaped dimer with two unusual alpha-helical extensions. Mol. Cell.
Ditch eld, C., V.L. Johnson, A. Tighe, R. Ellston, C. Haworth, T. Johnson, A.
Mortlock, N. Keen, and S.S. Taylor. 2003. Aurora B couples chromo-
some alignment with anaphase by targeting BubR1, Mad2, and Cenp-E
to kinetochores. J. Cell Biol. 161:267–280.
Earnshaw, W.C., and R.L. Bernat. 1991. Chromosomal passengers: toward an
integrated view of mitosis. Chromosoma. 100:139–146.
Fischle, W., B.S. Tseng, H.L. Dormann, B.M. Ueberheide, B.A. Garcia, J.
Shabanowitz, D.F. Hunt, H. Funabiki, and C.D. Allis. 2005. Regulation of
HP1-chromatin binding by histone H3 methylation and phosphorylation.
Nature. 438:1116–1122.
Gassmann, R., A. Carvalho, A.J. Henzing, S. Ruchaud, D.F. Hudson, R. Honda,
E.A. Nigg, D.L. Gerloff, and W.C. Earnshaw. 2004. Borealin: a novel
chromosomal passenger required for stability of the bipolar mitotic
spindle. J. Cell Biol. 166:179–191.
Gruneberg, U., R. Neef, R. Honda, E.A. Nigg, and F.A. Barr. 2004. Relocation
of Aurora B from centromeres to the central spindle at the metaphase to
anaphase transition requires MKlp2. J. Cell Biol. 166:167–172.
Hauf, S., R.W. Cole, S. LaTerra, C. Zimmer, G. Schnapp, R. Walter, A. Heckel,
J. van Meel, C.L. Rieder, and J.M. Peters. 2003. The small molecule
Hesperadin reveals a role for Aurora B in correcting kinetochore-
microtubule attachment and in maintaining the spindle assembly
checkpoint. J. Cell Biol. 161:281–294.
Hirota, T., J.J. Lipp, B.H. Toh, and J.M. Peters. 2005. Histone H3 serine 10 phos-
phorylation by Aurora B causes HP1 dissociation from heterochromatin.
Nature. 438:1176–1180.
Honda, R., R. Korner, and E.A. Nigg. 2003. Exploring the functional interac-
tions between Aurora B, INCENP, and survivin in mitosis. Mol. Biol.
Cell. 14:3325–3341.
Kang, J., I.M. Cheeseman, G. Kallstrom, S. Velmurugan, G. Barnes, and
C.S. Chan. 2001. Functional cooperation of Dam1, Ipl1, and the inner
centromere protein (INCENP)-related protein Sli15 during chromosome
segregation. J. Cell Biol. 155:763–774.
Keen, N., and S. Taylor. 2004. Aurora-kinase inhibitors as anticancer agents.
Nat. Rev. Cancer. 4:927–936.
Klein, U.R., E.A. Nigg, and U. Gruneberg. 2006. Centromere targeting of the
chromosomal passenger complex requires a ternary sub-complex of
Borealin, Survivin, and the N-terminal domain of INCENP. Mol Biol
Cell. 10.1091/mbc.E05-12-1133.
Lens, S.M., J.A. Rodriguez, G. Vader, S.W. Span, G. Giaccone, and R.H.
Medema. 2006. Uncoupling the central spindle-associated function of the
chromosomal passenger complex from its role at centromeres. Mol. Biol.
Cell. 17:1897–1909.
Li, F., G. Ambrosini, E.Y. Chu, J. Plescia, S. Tognin, P.C. Marchisio, and D.C.
Altieri. 1998. Control of apoptosis and mitotic spindle checkpoint by
survivin. Nature. 396:580–584.
Mackay, A.M., D.M. Eckley, C. Chue, and W.C. Earnshaw. 1993. Molecular
analysis of the INCENPs (inner centromere proteins): separate domains
are required for association with microtubules during interphase and with
the central spindle during anaphase. J. Cell Biol. 123:373–385.
Muchmore, S.W., J. Chen, C. Jakob, D. Zakula, E.D. Matayoshi, W. Wu, H.
Zhang, F. Li, S.C. Ng, and D.C. Altieri. 2000. Crystal structure and mu-
tagenic analysis of the inhibitor-of-apoptosis protein survivin. Mol. Cell.
Murata-Hori, M., M. Tatsuka, and Y.L. Wang. 2002. Probing the dynamics
and functions of aurora B kinase in living cells during mitosis and
cytokinesis. Mol. Biol. Cell. 13:1099–1108.
Nousiainen, M., H.H. Sillje, G. Sauer, E.A. Nigg, and R. Korner. 2006.
Phosphoproteome analysis of the human mitotic spindle.
Proc. Natl.
Acad. Sci. USA. 103:5391–5396.
Pereira, G., and E. Schiebel. 2003. Separase regulates INCENP-Aurora B
anaphase spindle function through Cdc14. Science. 302:2120–2124.
Romano, A., A. Guse, I. Krascenicova, H. Schnabel, R. Schnabel, and M. Glotzer.
2003. CSC-1: a subunit of the Aurora B kinase complex that binds to the
Survivin-like protein BIR-1 and the Incenp-like protein ICP-1. J. Cell
Biol. 161:229–236.
Sessa, F., M. Mapelli, C. Ciferri, C. Tarricone, L.B. Areces, T.R. Schneider, P.T.
Stukenberg, and A. Musacchio. 2005. Mechanism of Aurora B activation
by INCENP and inhibition by hesperadin. Mol. Cell. 18:379–391.
Severson, A.F., D.R. Hamill, J.C. Carter, J. Schumacher, and B. Bowerman.
2000. The aurora-related kinase AIR-2 recruits ZEN-4/CeMKLP1 to the
mitotic spindle at metaphase and is required for cytokinesis. Curr. Biol.
Vader, G., J.J. Kauw, R.H. Medema, and S.M. Lens. 2006. Survivin mediates
targeting of the chromosomal passenger complex to the centromere and
midbody. EMBO Rep. 7:85–92.
Verdecia, M.A., H. Huang, E. Dutil, D.A. Kaiser, T. Hunter, and J.P. Noel. 2000.
Structure of the human anti-apoptotic protein survivin reveals a dimeric
arrangement. Nat. Struct. Biol. 7:602–608.
Vong, Q.P., K. Cao, H.Y. Li, P.A. Iglesias, and Y. Zheng. 2005. Chromosome
alignment and segregation regulated by ubiquitination of survivin.
Science. 310:1499–1504.
Page 4
Wheatley, S.P., S.E. Kandels-Lewis, R.R. Adams, A.M. Ainsztein, and W.C.
Earnshaw. 2001. INCENP binds directly to tubulin and requires dy-
namic microtubules to target to the cleavage furrow. Exp. Cell Res.
Wheatley, S.P., A.J. Henzing, H. Dodson, W. Khaled, and W.C. Earnshaw. 2004.
Aurora-B phosphorylation in vitro identi es a residue of survivin that
is essential for its localization and binding to inner centromere protein
(INCENP) in vivo. J. Biol. Chem. 279:5655–5660.
Yoon, H.J., and J. Carbon. 1999. Participation of Bir1p, a member of the inhibi-
tor of apoptosis family, in yeast chromosome segregation events. Proc.
Natl. Acad. Sci. USA. 96:13208–13213.
Page 5
    • "From late prophase to metaphase CPC localizes to the inner centromere, playing a role in formation and stability of the bipolar mitotic spindle, kinetochore assembly, correction of nonbipolar chromosome-spindle attachments, and control of the spindle checkpoint (Figure 3). At the beginning of anaphase CPC relocates to the midzone of the mitotic spindle and to the cell cortex, remaining evident in the midbody of telophasic cells where it modulates the activity of several proteins involved in spindle dynamics, cleavage furrow formation, and completion of cytokinesis (Figure 3) [18, 19, 36, 37]. "
    [Show abstract] [Hide abstract] ABSTRACT: Anaplastic thyroid cancers (ATC) are among the most aggressive human neoplasms with a dire prognosis and a median survival time of few months from the diagnosis. The complete absence of effective therapies for ATC renders the identification of novel therapeutic approaches sorely needed. Chromosomal instability, a feature of all human cancers, is thought to represent a major driving force in thyroid cancer progression and a number of mitotic kinases showing a deregulated expression in malignant thyroid tissues are now held responsible for thyroid tumor aneuploidy. These include the three members of the Aurora family (Aurora-A, Aurora-B, and Aurora-C), serine/threonine kinases that regulate multiple aspects of chromosome segregation and cytokinesis. Over the last few years, several small molecule inhibitors targeting Aurora kinases were developed, which showed promising antitumor effects against a variety of human cancers, including ATC, in preclinical studies. Several of these molecules are now being evaluated in phase I/II clinical trials against advanced solid and hematological malignancies. In the present review we will describe the structure, expression, and mitotic functions of the Aurora kinases, their implications in human cancer progression, with particular regard to ATC, and the effects of their functional inhibition on malignant cell proliferation.
    Full-text · Article · Jul 2014
    • "This underscores that substrate specificity of the Aurora A and Aurora B kinases is predominantly dictated by specific localization of these kinases. Indeed, the prevailing view is that the non-enzymatic subunits of the CPC activate Aurora B and guide it to its different locations in the dividing cell to encounter and phosphorylate substrates and hence to execute its local functions (Carmena et al. 2012b; Vader et al. 2006b). "
    [Show abstract] [Hide abstract] ABSTRACT: The ultimate goal of cell division is equal transmission of the duplicated genome to two new daughter cells. Multiple surveillance systems exist that monitor proper execution of the cell division program and as such ensure stability of our genome. One widely studied protein complex essential for proper chromosome segregation and execution of cytoplasmic division (cytokinesis) is the chromosomal passenger complex (CPC). This highly conserved complex consists of Borealin, Survivin, INCENP, and Aurora B kinase, and has a dynamic localization pattern during mitosis and cytokinesis. Not surprisingly, it also performs various functions during these phases of the cell cycle. In this review, we will give an overview of the latest insights into the regulation of CPC localization and discuss if and how specific localization impacts its diverse functions in the dividing cell.
    Full-text · Article · Oct 2013
    • "The CPC associates with chromatin during G2, then moves to the inner centromeres by prometaphase-metaphase. In anaphase, the CPC translocates to the CS MTs and the equatorial cortex [Adams et al., 2000; Vagnarelli and Earnshaw, 2004; Vader et al., 2006; Szafer-Glusman et al., 2011; van der Waal et al., 2012]. The D. melanogaster genome encodes two Borealin paralogs, Borealin-related (Borr) and Australin [Aust; Gao et al., 2008]; the latter replaces Borr in male meiosis. "
    [Show abstract] [Hide abstract] ABSTRACT: Cytokinesis separates the genomic material and organelles of a dividing cell equitably into two physically distinct daughter cells at the end of cell division. This highly choreographed process involves coordinated reorganization and regulated action of the actin and microtubule cytoskeletal systems, an assortment of motor proteins, and membrane trafficking components. Due to their large size, the ease with which exquisite cytological analysis may be performed on them, and the availability of numerous mutants and other genetic tools, Drosophila spermatocytes have provided an excellent system for exploring the mechanistic basis for the temporally programmed and precise spatially localized events of cytokinesis. Mutants defective in male meiotic cytokinesis can be easily identified in forward genetic screens by the production of multinucleate spermatids. In addition, the weak spindle assembly checkpoint in spermatocytes, which causes only a small delay of anaphase onset in the presence of unattached chromosomes, allows investigation of whether gene products required for spindle assembly and chromosome segregation are also involved in cytokinesis. Perhaps due to the large size of spermatocytes and the requirement for two rapid-fire rounds of division without intervening S or growth phases during meiosis, male meiotic mutants have also revealed much about molecular mechanisms underlying new membrane addition during cytokinesis. Finally, cell type-specific differences in the events that set up and complete cytokinesis are emerging from comparison of spermatocytes with cells undergoing mitosis either elsewhere in the organism or in tissue culture. © 2012 Wiley Periodicals, Inc.
    Full-text · Article · Nov 2012
Show more