Journal of Cancer Therapy, 2013, 4, 1341-1354 Published Online October 2013 (
Cks1: Structure, Emerging Roles and Implications in
Multiple Cancers
Vinayak Khattar1, Jaideep V. Thottassery1,2
1Southern Research Institute, Birmingham, USA; 2University of Alabama Comprehensive Cancer Center, Birmingham, USA.
Received August 12th, 2013; revised September 10th, 2013; accepted September 17th, 2013
Copyright © 2013 Vinayak Khattar, Jaideep V. Thottassery. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Deregulation of the cell cycle results in loss of normal control mechanisms that prevent aberrant cell proliferation and
cancer progression. Regulation of the cell cycle is a highly complex process with many layers of control. One of these
mechanisms involves timely degradation of CDK inhibitors (CKIs) like p27Kip1 by the ubiquitin proteasomal system
(UPS). Cks1 is a 9 kDa protein which is frequently overexpressed in different tumor subtypes, and has pleiotropic roles
in cell cycle progression, many of which remain to be fully characterized. One well characterized molecular role of
Cks1 is that of an essential adaptor that regulates p27Kip1 abundance by facilitating its interaction with the SCF-Skp2 E3
ligase which appends ubiquitin to p27Kip1 and targets it for degradation through the UPS. In addition, emerging research
has uncovered p27Kip1-independent roles of Cks1 which have provided crucial insights into how it may be involved in
cancer progression. We review here the structural features of Cks1 and their functional implications, and also some re-
cently identified Cks1 roles and their involvement in breast and other cancers.
Keywords: Cks1; Cks2; Skp2; Cdk1; p27; Kip1; p130; Rb2; CKI; Ubiquitination; Proteasome; ERK1/2
1. Introduction
Regulation of the cell cycle is crucial for cellular prolif-
eration and survival [1,2]. The engines that drive the cell
cycle include cyclin dependent kinases (CDKs) and their
activating cyclin subunits which oscillate during the cell
cycle and thus modulate the activity of CDKs at specific
points in various cell cycle phases [3]. Another level of
control requires the action of cyclin dependent kinase
inhibitors (CKIs) on CDKs [4]. These CKIs, along with
other cell cycle substrates are regulated by precise and
coordinated proteasomal degradation [5,6]. This in turn
can regulate the activities and abundance of other sub-
strates [5,6].
The ubiquitin proteasomal system (UPS) employs a
series of activating (E1), conjugating (E2) and ligase (E3)
enzymes and appends ubiquitin chains to substrates, and
directs them to timely degradation by the proteasomal
machinery [7]. For instance a crucial step in regulating
mammalian G1-S transition is one which involves the
degradation of p27Kip1 by the UPS, which is required for
full activation of cyclin E-CDK2 complexes [8,9]. Fol-
lowing its phosphorylation on Thr-187 by cyclin E-Cdk2,
p27Kip1 is ubiquitinated by the SCF-Skp2 E3 ligase [10].
Ganoth et al. demonstrated that fully reconstituted SCF-
Skp2 only ubiquitinates p27Kip1 when it is supplemented
with Cks1 [11,12]. Investigations revealed that Cks1 in-
teracts with the substrate recognition component in this
complex, Skp2, and facilitates its p27Kip1 ubiquitination
activity [12,13]. Until recently this was the only well
characterized molecular role for Cks1 in mammalian
systems. However, emerging research reveals many more
diverse and p27Kip1 independent roles of Cks1 that en-
compass growth signaling pathways [14-25], apoptosis
[25] and even DNA damage responses [26,27].
Cks1 was discovered in 1986 in a screen that identified
genes that allow temperature sensitive cdc2 mutants in
yeast to grow at the restrictive temperature [28-30]. The
screen identified a molecule called Suc1 (Suppressor of
cdc2) which when present on multicopy plasmids in
Schizosaccharomyces pombe could rescue cells mutated
in their cdc2 [28]. The study hinted that the action of-
Suc1 was specific to cdc2 suggesting direct interaction
between the two [28,29]. Indeed it is now recognized that
Cks1 (Suc1 in S. pombe) does interact with CDKs at a
site that is distinct from their ATP binding or cyclin
binding sites [31-33]. Further characterization revealed
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Cks1: Structure, Emerging Roles and Implications in Multiple Cancers
that overexpression or mutations in Suc1 caused defects
in the cell cycle and in viability showing that this gene
was crucial for cell cycle progression [34].
2. Structure and Functional Implications
2.1. Sequence, Secondary and Higher
Order Structure
The sequence of the Cks family of proteins is highly con-
served across species [31,35,36]. Exploiting this similar-
ity Richardson et al. designed degenerate primers allow-
ing them to clone the human orthologs CksHs1 and
CksHs2 from a HeLa cDNA library [37]. Comparison of
CksHs1 and CksHs2 reveals 81% identity between the two
molecules [37]. The evolutionary logic behind this con-
servation can be appreciated in the context of the crucial
role of Cks1 in cell cycle and its interactions with CDKs
[38]. For instance both human Cks proteins have identities
higher than 50% when compared with both the fission and
budding yeast Cks sequences and are capable of rescuing
a null mutation in the S. cerevisiae Cks1 gene [33,37].
Although there is a high level of conservation among
Cks1 sequences across species, the length of Cks1 in S.
Cerevisiae and S. pom be is 150 and 113 residues respec-
tively, while the human orthologs, CksHs1 and CksHs2,
are both 79 amino acids long [31,35,36]. The major dif-
ferences that account for this difference in length are two
extensions at the N and C-terminals and a 9 amino acid
insertion sequences in yeast Cks sequences not found in
CksHs1 or CksHs2 [32]. The C-terminal extension in
yeast sequences includes a 16 residue long polyglutamine
tail and it has been observed that these Cks1 molecules
can form fibrillar aggregates characterized by presence of
specific hydrogen bonding between polyglutamine se-
quences [35,36,39]. The characteristics of these aggre-
gates were found to be very similar to those observed in
amyloid fibrils or aggregates observed in other polyglu-
tamine deposition diseases on firm that you have the cor-
rect template for your paper size.
CksHs1 and CksHs2 have key structural differences at
higher levels of structural organization despite their re-
markable sequence identity. Arvai et al. determined the
structure of Cks1Hs1 at a resolution of 2.9 A, and ob-
served that the domain architecture and subunit confor-
mation for CksHs1 and Cks1Hs2 are dramatically dif-
ferent [31]. Although theoretically both CksHs1 and
CksHs2 can exist in monomeric and dimeric forms in
vitro, it appears that Cks1Hs1 is more stable in mono-
meric form whereas CksHs2 was observed in primarily
dimeric and even hexameric forms [31]. In vivo it is pre-
dicted that binding of CDKs and metal ions influences
that stability and predominance of a particular form over
the other [31,40].
Nevertheless CksHs1 does crystallize as a dimer with
anionic cofactors like vanadate, tungstate or phosphate
[31,40]. The CksHs1 dimer utilizes a crucial hydrogen
bond between residues Tyr 8 present in the β1 strand of
each molecule [31]. The Cks1Hs1 monomer is a single
polypeptide chain folded in a single domain comprising
four anti-parallel β sheets sandwiching two α-helices [31].
Starting from the N-terminus the sequence of secondary
structural elements includes two anti-parallel β sheets β1
and β2 followed by two short α helices and finally two
anti-parallel β sheets β3 and β4 [31]. Following crystal-
lization these monomers can assemble into dimeric form
with eight β sheets forming a twisted structure due to a
tilt of 50 degrees between the two adjacent β strands [31].
Despite the fact that both CksHs1 and CksHs2 molecules
can form dimers, the folding of a small sequence con-
served region between Glu 61 and His 65 results in dra-
matically different conformations for the β4 strand re-
sulting in he characteristic β strand exchange form ob-
served in CksHs2 [31]. Thus, depending on the confor-
mation of this highly conserved region forming a β-hinge
between β3 and β4 strands, Cks proteins can exist in two
forms [31]. When this hinge region is in an extended
conformation, it facilitates the β4 strand from one
monomer to fold out and interact with secondary struc-
tural elements of the other monomer [31]. Similarly the
corresponding β4 strand from the second monomeric
domain extends out and “squeezes” itself between sec-
ondary structural elements on the other monomer of the
Cks molecule thus resulting in characteristic structure
termed β strand exchange dimer [31]. On the other hand
in a closed conformation this hinge region is more or-
dered and will exist as a β bend preventing any such
strand exchange between monomers [31]. In CksHs1 the
β hinge region is in this closed conformation and hence
does not allow any β strand exchange between the mo-
nomers [31]. On the other hand this conserved region is
conformationally different in CksHs2 allowing it to as-
semble as a β strand exchanged dimer [31].
These subtle differences in the β hinge region that
leads to dramatically different subunit conformation sug-
gests a theory where a specific stimulus or cell cycle
event may trigger a change from one form to another as a
part of a regulatory mechanism [31]. This in turn could
lead to changes in critical interactions between Cks and
its partner proteins leading to other downstream physio-
logical consequences [31]. Although, whether in fact
such changes in domain architecture of CksHs1 do play a
part in cell physiology remains speculation for the time
being, Arvai et al. have pointed out that critical residues
such as Tyr 12, Tyr 19 and Tyr 57 are exposed in the
single domain fold whereas these regions are masked in
dimeric or hexameric forms [31].
2.2. Functional Implications of Structural
Features in Cks1
Functionally speaking Cks1 structure is characterized by
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Cks1: Structure, Emerging Roles and Implications in Multiple Cancers 1343
the presence of three regions including a cdc2/CDK
binding region, a Skp2 binding region and an anion/
phosphate binding pocket [31,32,41-43] (see Table 1 for
the key residues mediating the interactions in these func-
tional regions). Another striking feature of Cks1 structure
is that the CksHs1 molecule shows a strong homology to
the N-lobe domain of CDK2 [31,32,41-43]. That Cks1
binds to cdc28 and cdc2 was already established during
early coimmunoprecipitation studies with yeast homo-
logs of Cks1 [44]. Similarly it was later demonstrated
that Xe-p9 could also interact with Cdc2/cyclinB com-
plexes [45]. The crystal structure of human CDK2 in
complex with CksHS1 revealed that Cks1 utilizes all four
beta sheets for this interaction and binds specifically to
the C-terminal lobe of CDK [32]. Also it was revealed
that the CDK domain does not interact with the cyclin
binding sites or regulatory phosphate binding sites [32].
Cks1 can bind to CDK only in its monomer conformation
and uses specific hydrophobic residues (see Table 1) as
well as the conserved β-hinge region [32]. On the other
hand the opening of this β hinge, which is the character-
istic feature of the beta strand exchanged dimer does not
allow Cks to bind to CDK2 [32].
The ternary complex of Skp1-Skp2-Cks1 in associa-
tion with a phosphorylated p27Kip peptide elucidated by
Pavletich et al. has provided significant insights into how
Cks1 influences recognition of p27Kip1 by the SCF com-
plex [42]. It is a sickle shaped binary structure where
Skp1 and the F-box domain of Skp2 form the handle and
the Skp2 leucine rich repeat (LRR) domain forms the
curved blade [42]. The C-terminal tail of Skp2 at the end
of tenth LRR curves inwards and interacts with first LRR.
The Cks1 molecule docks into this concave groove form-
Table 1. Cks1 structural features and their functional im-
Property Residue Region and Contacts
Pocket (Binds
pThr187 of
Between α2 and β3
β4 (all involved in
Cdk binding
Y19, H21, M23
Y57, M58
H60, P62, I66, L68, R70
β1 (hydrophobic)
β2 (hydrophobic)
Between β2 and β3
β4 (hydrophobic)
β4 (H-bonding)
Skp2 binding
E40, S41, E42, N45
L31, P33
H36, M38
α2 (H-bonding)
 α1 (van der Waals)
 α2 (van der Waals)
I6, Y7, D10
M23, Q49
β1 (H-bonding)
between α2 and β3
ed by the LRR and C-terminal tail of Skp2. Three key
residues (see Table 1) of Cks1 are required for H-bond-
ing interactions with Skp2 and map into the 2 helix of
Cks1 [41,42]. Phosphorylated p27Kip1 is recognized by
phosphate binding pocket of Cks1 and p27Kip1 forms re-
gions of contacts with both Cks1 and Skp2 by inserting a
crucial Glu185 residue in the interface formed between
Cks1 and Skp2 [41,42]. Hydrogen bonding between
highly conserved Skp2 residues (Trp265, Arg294,
Asp319, and Arg344 side chains) and those of Cks1
(Ser41, Glu40, and Asn45 side chains and Ser41 car-
bonyl group) is a crucial prerequisite for Cks1-Skp2 in-
teraction and hence altering these Cks1 residues is
known to compromise the p27Kip1 ubiquitination activity
of the SCF complex [41,42]. The residues Ser41 and Asn
45, are replaced by Glu and Arg residues in CksHs2 pre-
cluding its interaction with Skp2 [41,42]. Yeast Skp2 is
not known to interact with Cks1, although Cks1 in yeast
does play a role in the multi-site phosphorylation of Sic1,
the CDK inhibitor that is homologous to mammalian
p27Kip1 [46].
The ubiquitination of p27Kip1 is preceded by its phos-
phorylation at residue Thr187 which is then recognized by
the phosphate binding pocket present in Cks1 [31,41,42,
47,48]. Two anion binding pockets are present near the
dimer interface within a crevice formed by the dimer
association [31]. In fact negatively charged moieties like
vanadate or tungstate were used to facilitate crystalliza-
tion of CksHs1 by Arvai et al. [40]. Crucial van der
Walls contacts and hydrogen bonding contacts from
residues Lys11, Arg20 and Arg71 and to the main chain
nitrogen atom of Ser51 stabilize the interaction with
these moieties [42].
3. Diverse Cellular Functions of Cks1
Cks1 roles can be broadly classified into four categories:
1) roles in modulating cell cycle, 2) roles in transcription,
3) roles in growth signaling pathways, and 4) other
emerging roles. Excellent reviews describing some of
these functions of Cks1 are available [49-53].
3.1. Cks1 Roles in Modulating the Cell Cycle
The evidence for Cks1 modulating the cell cycle was
provided by Tang and Reed where it was reported that
loss of Cks1 in S. cerevisiae causes defects in both G1-S
and G2-M transition [54]. However the mechanism by
which Cks1 regulates G1-S transitions in mammalian
systems was elucidated in two independent reports by
Ganoth et al. and Spruck et al. which showed that Cks1
is indispensable for proteasomal degradation of p27Kip1
[12,13]. Ganoth et al. showed that a fully reconstituted
SCF-Skp2 complex cannot ubiquitinate p27 in-vitro
unless it was supplemented by a crucial factor (Factor I)
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Cks1: Structure, Emerging Roles and Implications in Multiple Cancers
derived from the unbound fraction of the HeLa cell ex-
tracts fractionated on DEAE–cellulose columns [12].
Further purification and characterization of this unknown
factor revealed that this factor was Cks1 [12]. Further-
more this report established that Cks1’s role in p27Kip1
degradation was specific to the SCF-Skp2 ligase since it
had no impact on the activity of other ubiquitin ligases
like SCF β-TrCP [12]. Spruck et al. utilized MEFs de-
rived from Cks1/ mice [13]. Cks1/ mice exhibit a
smaller body size, which is possibly due to proliferative
abnormalities (due to accumulation of p27Kip1 in somatic
cells during embryonic development) [13]. Interestingly
the roles of Cks1 in p27Kip1 degradation have been sug-
gested to be independent of its interactions with CDKs.
A Cks1 mutant defective in CDK binding (E63Q) has
been shown to be capable of p27Kip1 ubiquitination [13].
On the other hand other mutations in the CDK2 binding
site of Cks1 do reduce the ability of cyclin A-CDK2 to
promote p27Kip1 ubiquitination [41]. Although phos-
phorylation of p27Kip1 on residues Thr-187 by cyclin
E/A-CDK2 complex is a crucial prerequisite for its rec-
ognition and proteasomal targeting by the SCF-Skp2
ubiquitin ligase, whether the interactions of Cks1 with
CDK2 itself have any impact on its p27Kip1 ubiquitination
activity remains controversial [13,41,42].
Three models have been suggested to describe the role
of Cks1 in p27Kip1 ubiquitination [50]. The first model
suggests that binding of Cks1 to the C-terminal of Skp2
results in a necessary conformational change that allows
the Skp2 to interact efficiently with its phosphorylated
substrate, p27Kip1. This model depicts a binding site of
Cks1 wherein Cks1 docks in a concave groove formed by
the LRR region and the C-terminal tail of Skp2 [42,50].
It is suggested that interaction of Cks1 with the C-ter-
minal tail region of the Skp2 molecule “nudges” the oc-
cluding LRR region and allows efficient interaction be-
tween LRR and the phosphorylated substrate [42,50,55].
The second model suggests that Cks1 may physically act
as an adaptor or bridge between phosphorylated substrate
p27Kip1 and F-box protein Skp2 [42]. It is possible that
the phosphate binding site of Cks1 recognizes phos-
phorylated p27Kip1 which is then brought in close prox-
imity to Skp2 for ubiquitination [42]. Although it has
been shown that Cks1 interaction with CDK2 is not nec-
essary for p27Kip1 degradation, it has been suggested in a
third model that Cks1-CDK2 binding pulls out the
p27Kip1-cyclin A-Cdk2 complex and favors its interaction
with SCF-Skp2 complex [42]. Although further genetic
and biochemical studies are required to distinguish be-
tween these possibilities, the role of Cks1 in p27Kip1 deg-
radation is indisputable.
Cks1 also regulates the proteasomal degradation of
p130/Rb2 which is both a pocket protein and an inhibitor
of CDK2 [56,57]. The expression of p130 is largely re-
stricted to G0 phase of the cell cycle [56,57]. Like
p27Kip1 the turnover of p130 is regulated proteasomally
[58]. As proliferating cells enter from G0 phase to G1,
p130 gets phosphorylated by CDK4/6 complexes and is
proteasomally degraded by a process which employs the
SCF-Skp2 E3 ubiquitin ligase complex [58]. In fact loss
of either Skp2 or Cks1 impairs proteasomal stability of
p130 as evidenced by its accumulation in asynchronous
or thymidine arrested Skp2/ and Cks1/ fibroblasts [58].
Thus Cks1 is responsible not only for regulating the
p27Kip1 degradation but also plays a pivotal role in de-
termining p130 stability in proliferating cells [58].
Cks1 has also been implicated in the degradation of
mitotic substrates by regulating the APC/C ubiquitin li-
gase and spindle assembly checkpoint (SAC), which is
crucial for orchestrating mitotic timing [59-62]. The SAC
fine-tunes the timing of proteasomal degradation through
APC/C ubiquitin ligase by inactivating its coactivator
Cdc20 [63,64]. This in turn prevents premature degrada-
tion of APC/C mitotic substrates like securin and cyclin
B1 ensuring accurate sister chromatid separation before
mitotic exit [63,64]. However other APC/C substrates
like cyclin A are degraded even though the SAC is still
active [65]. Studies by Di Fiore et al. and Wolthius et al.
have explained this paradox by showing that the N-ter-
minus of cyclin A competes with SAC proteins to bind to
Cdc20 [66,67]. Following this Cks1 recruits the cyclin
A-cdc20 complex to a phosphorylated APC/C ubiquitin
ligase, triggering cyclin A ubiquitination and subsequent
proteasomal degradation. [66,67]. Furthermore it was
demonstrated that the anion binding site of Cks1 is cru-
cial for the SAC independent degradation of cyclin A
Loss of Cks1 also results in impaired mitotic passage
in yeast and in Xenopu s egg extracts [45,54]. In Xenopus
egg extracts, Cks1 is crucial for dephosphorylation of
Y15 residue of CDK1 [45]. Cks1 promotes MPF depen-
dent phosphorylation of cdc25c phosphatases, wee 1 and
myt1 kinases, all molecules that participate in CDK1
activation by removing inhibitory phosphorylation from
Cdk1 [45]. Xe-p9 (Xenopus homologue of Cks1) is also
known to promote cyclin B1 degradation [68,69]. More
specifically Xe-p9 regulates mitotic exit by stimulating
phosphorylation of cdc27, another important component
of the APC/C complex that targets cyclin B1 and several
other mitotic molecules for proteasomal degradation,
thus orchestrating mitotic exit in these cells [68,69].
Studies in our laboratory have shown that loss of Cks1 in
MCF-7 breast cancer cells leads to blockade in mitotic
entry with corresponding loss of CDK1 [70]. Further-
more the mitotic block can be rescued by reintroduction
of exogenous CDK1 [70]. A report by Martinsson-Ahl-
zen et al. has also demonstrated that loss of Cks1 in
MEFs and HeLa cells results in cell cycle arrest in G2
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Cks1: Structure, Emerging Roles and Implications in Multiple Cancers 1345
phases which can be reversed reintroduction of cyclin B1
[71]. Interestingly Cks1 loss does not alter cell cycle pro-
files in human mammary epithelial cells (HMECs) or
normal human lung fibroblasts [70,72].
Although G1-S defects following Cks1 loss in mam-
malian cells can be accounted for by p27Kip1 accumula-
tion, recent reports have indicated that some defects can
also be explained in part by p27Kip1 independent mecha-
nisms [73]. In studies reported by Keller et al. it was
found that CDK1 kinase activity of the Cks1/ MEF
cells was not altered whereas there is considerable loss in
CDK2 kinase activity [73]. Furthermore concomitant loss
of p27Kip1 in Cks1/ MEF did not rescue this loss in
Cdk2 kinase activity indicating that part of G1-S defects
observed are p27Kip1 independent and a direct cones-
quence of Cks1 interaction with CDK2 activity [73]. In
fact a report by Liberal et al. has shown that Cks1 can
override DNA damage response by increasing CDK2
kinase activity and overriding the inhibitory effects of
Y15 phosphorylation on CDK2 [27].
3.2. Cks1 Roles in Transcription
Recently Cks1 has also been implicated in transcriptional
regulation [71,74-77]. In fact some of these transcrip-
tional roles also indicate other ways by which Cks1
might be involved in regulating cell cycle transitions [71,
76]. For instance, Cdc20 has been shown to be a tran-
scriptional target of Cks1 [76]. Cdc20 is a regulator
which associates with and modulates the activity of the
APC ubiquitin ligase during distinct phases of cell cycle
[78]. It was shown that Cks1 is essential for dissociation
of Cdc28 from Cdc20 promoter and recruitment of spe-
cific proteasomal subunits like Rpt1, Pre1 on this pro-
moter [76]. It has been suggested that this periodic asso-
ciation and dissociation events on the Cdc20 promoter
facilitates remodeling of transcriptional complexes dock-
ed on the Cdc20 promoter [76]. It has also been recently
reported that that Cks1 plays a role in GAL1 transcrip-
tion, whereby Cks1, CDK1 and the 19S subunit of the
proteasome are recruited to the GAL1 promoter, specifi-
cally attaching to the histone H4 amino-terminal tail of
the chromatin [74]. This activity has been reported to
alter nucleosome density and evict nucleosomes from the
chromatin region thereby inducing GAL1 transcription
[74]. Cks1 has also been shown to transcriptionally
regulate the expression of cdc2, cyclin B and cyclin A in
mammalian cells [71].
The regulation of Cks1 gene expression itself is now
known to be regulated through transcriptional mecha-
nisms [79-87]. Cks1 mRNA levels start rising in late G1
reaching a peak before the onset of S-phase [88]. An-
other peak is observed at G2/M phase of the cell cycle
[37]. Various reports have provided insights into possible
transcriptional regulators for Cks1 [79-86]. Mutating a
potential CDE/CHR (cell cycle dependent element and
cell cycle genes homology region) tandem repeat within
Cks1 promoter compromises transcriptional activation of
Cks1 indicating that this element acts as a possible tran-
scriptional regulator [87]. Although Cks1 does not have
p53 binding site, forced induction of p53 represses
mRNA and protein expression of Cks1 possibly due to
p53 dictated repression of Cks1 promoter [87]. On the
other hand NF-Y, FoxM1, and Myc are known to act as
transcriptional activators for Cks1 [80,81,83,85,87]. In
fact Myc induced Cks1 activation has been proposed to
be a switch that triggers p27Kip1 loss and subsequent cell
proliferation and tumorigenesis by Keller et al. [81].
In primary T-lymphocytes CD28 along with T-cell re-
ceptor (TCR) provides a co-stimulatory signal that is
required for T cell activation and entry into S-phase [89,
90]. CD28 co-stimulatory signals downregulate p27Kip1
by inducing transcription of Skp2 and Cks1, thus en-
hancing its proteasomal degradation [79]. TGF-treatment
of mink lung epithelial cells and Hep3B cells also de-
creases Cks1 mRNA transcripts, and this loss of Cks1
has been known to compromise p27Kip1 ubiquitination,
and also triggers Skp2 autoubiquitination and degrada-
tion [86]. Furthermore, B-Raf and cyclin D1 also down-
regulate Cks1 expression at the mRNA and protein levels
[15]. Despite many reports of Cks1 roles in transcription
and the transcriptional regulation of Cks1 by other pro-
teins, many gaps remain in our knowledge regarding the
mechanisms of both these phenomena and require further
3.3. Cks1 Roles in Growth Signaling Pathways
The roles of Cks1 in growth factor signaling pathways
have started to emerge with few studies suggesting the
involvement of Cks1 in MAPK, JAK-STAT and NF-B
pathways [13-24]. Despite its crucial role in cell cycle
and cancer progression, mechanistic studies regarding
Cks1 role in growth signaling mechanisms are lacking.
Cks1 siRNA knockdown decreases ERK1/2 phosphory-
lation and triggers apoptosis in breast cancer cells MDA-
MB-231 whereas its overexpression inhibits apoptosis
and increases ERK1/2 phosphorylation hinting at a Cks1
modulated signaling event in this important pathway [25].
Another study showed that Cks1 shRNA mediated
knockdown leads to decrease in ERK1/2, MEK and
STAT phosphorylation in multiple myeloma cell lines
KMS28PE, OCI-MY5 and XG-1 whereas forced over-
expression of Cks1 activates ERK1/2 and STAT phos-
phorylation in the later two cell lines [21]. Surprisingly
Skp2 knockdown or p27Kip1 overexpression caused sup-
pression of ERK/MEK and JAK/STAT signaling indi-
cating that Cks1 may be involved at a crucial node of
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Cks1: Structure, Emerging Roles and Implications in Multiple Cancers
regulation of signaling events independently of Skp2 and
p27Kip1 [21].
Although the role of Cks1 upstream of these kinases at
the level of Ras GTPases and Raf kinases has not been
investigated, squamous cell carcinomas and lung adeno-
mas derived from RasH2 mice have been shown to ex-
hibit fluctuations in levels of Cks1 when treated with
genotoxic agents like 7,12-dimethylbenz[a]anthracene
(DMBA), urethane and N-ethyl-N-nitrosourea (ENU) [91].
It has also been shown that adaptor protein FGF receptor
2 (FRS2) associates with Cks1 and FGF dependent
phosphorylation of FRS2 releases Cks1 and causes con-
comitant p27Kip1 degradation in 3T3 cells [24]. Recently
the role of Cks1 in NF-B induced hepatocellular cancer
has also been reported whereby Cks1 transcriptionally
regulates IB and hence drives NF-B mediated IL-8 driv-
en hepatocellular carcinoma [19]. Given that Cks1 is
overexpressed in several different tumor types, its role as
a signaling modulator remains a fruitful and unexplored
avenue of research.
3.4. Other Roles of Cks1
Although the majority of research on Cks1 has been
conducted using yeast and mammalian systems, there are
a number of studies that have utilized other systems in-
cluding Xenopus laevis [45], Caenorhabditis elegans
[92], Drosophila melanogaster [93], Branchiostoma
belcheri tsingtauense [94], Leishmania Mexicana [95]
and Patella vulgate [96]. Cks1At, an A. thaliana ho-
molog of Cks1 was shown by Montagu et al. to bind to
arabidopsis CDKs Cdc2aAt and Cdc2bAt [97,98]. Fur-
ther characterization of Cks1At showed that overexpres-
sion of Cks1 in A. thaliana lead to a reduction in leaf
growth and root growth rates due to elongated G1 and
G2 phases of the cell cycle [99]. Similarly some parasitic
animal models have also been used in certain studies to
isolate and characterize homologs of the Cks1 protein.
For instance Leishmania mexicana has been used to iso-
late p12Cks1 which is the functional homolog of p13Suc1
counterpart found in yeast [95,100]. Not surprisingly this
protein was found to interact with yeast and bovine cdc2
as well as with CRK1 and SBCRK1 which are cdc2-
related kinases found in these parasites [95,100]. Recent
studies with Branchiostoma belcheri (Amphioxus) have
also suggested a potential developmental role of Cks1
[94]. Studies on Cks30 (Cks2 homologue in Drosophila)
and Cks85A (Cks1 homologue in Drosophhila) have also
demonstrated their role in female meiosis and mitosis
during embryonic development, and maintenance of cell
viability respectively [93,101-103].
In yet another report it was shown that Cks1 transcript
levels gradually increase with increasing follicle size in
bovine embryos possibly to ensure proper G2/M timing
of cell cycle in the embryonic cells [82]. Skp2 and Cks1
also have been shown to play a crucial role in S/G2 phase
transition during adipocyte differentiation in 3T3-L1
preadipocytes [104]. Yu et al. have also recently demon-
strated that a balance between Cks1 and Cks2 regulates
p27kip1 abundance and neuronal development in mouse
embryonic cells [26]. Collectively these reports suggest
novel roles of Cks family of protein in developmental
biology which await further characterization. More re-
cently Cks1 has also been shown to play a role in mito-
chondrial DNA replication regulating the mitochondrial
single-stranded DNA-binding protein (mtSSB) function
[105]. In another report demonstrating a p27kip1 inde-
pendent Cks1 role it has been shown that Cks1 and Cks2
overexpression are involved in overcoming the DNA
damage response following oncoprotein activation in
breast cancer cells [27].
4. Cks1—Implications in Breast and
Other Cancers
The importance of Cks1 in cancer progression can be
understood given its pleiotropic roles in diverse biologi-
cal processes that are known to be deregulated in cancer.
Cks1 is overexpressed in a majority of human cancers
and its expression is strongly correlated to tumor aggres-
siveness and dissemination of disease. Cks1 and its im-
plications in cancers have been addressed herein by re-
viewing studies of Cks1 transcript levels, protein expres-
sion and gene amplification (the Cks1 gene is located on
1q21) in normal and/or cancer derived samples from pa-
tient cohorts of different cancer subtypes and their corre-
lation to cancer clinicopathologic parameters. Because of
its known role in the SCF-Skp2 complex many of these
studies have also examined correlation of Cks1 expres-
sion to that of Skp2 and p27Kip1 or other cancer related
markers (such as p53 and Ki-67) [106]. In general Cks1
expression is strongly correlated with Skp2 expression
and inversely related to p27Kip1 expression [106-109].
However many studies including ours have reported dif-
ferent trends in expression pattern of these three genes
emphasizing potentially underappreciated p27Kip1 inde-
pendent mechanisms of Cks1 in cancer progression
[110-112]. Another area of focus involves studies that
attempt to determine the effect of Cks1 perturbation on
cancer phenotypes (e.g. colony formation, migration and
invasion, resistance to therapy etc.). For this discussion
we broadly focus on two areas a) Cks1 expression, roles
and implications in breast cancer, and b) Cks1 in other
4.1. Cks1 and Breast Cancer
We have found that normal mouse or rat tissues exhibit
nearly undetectable levels of Cks1 protein, whereas both
Copyright © 2013 SciRes. JCT
Cks1: Structure, Emerging Roles and Implications in Multiple Cancers 1347
Cks1 mRNA and protein levels are very high in corre-
sponding tumor tissues derived from mammary tumors
excised from different murine models of mammary tu-
morigenseis (erbB2, c-myc and polyoma middle-T
(PyMT) driven transgenic mice) and in carcinogen-initi-
ated rat models [110]. In agreement with these studies a
previous analysis of global gene expression patterns of
mammary tumors initiated by the PyMT oncogene ex-
pressed in the context of five different genomic back-
grounds revealed that Cks1 expression was greatly in-
creased in PyMT-transgenic mammary tumors [113].
Interestingly, we found that p27Kip1 levels were not re-
duced, and were in fact slightly higher in mammary tu-
mors initiated by erbB2, PyMT and MNU [110]. It is
also known that the relative abundance of Cks1 SAGE
tags in breast carcinoma tumor samples is higher com-
pared to that in normal human mammary epithelium
In one of the first studies that examined the role of
Cks1 overexpression in human breast cancer Slotky et al.
reported that Cks1 overexpression is associated with loss
of tumor differentiation, younger age of patients, lack of
expression of estrogen and progesterone receptors, de-
creased disease-free and overall survival [109]. Further-
more Cks1 and Skp2 expression was increased by estra-
diol in estrogen-dependent cell lines but were down-
regulated by tamoxifen [115]. In fact, in agreement with
these findings we have previously demonstrated that sta-
ble overexpression of Cks1 in human breast carcinoma
MCF-7 cells confers resistance to Faslodex (ICI-182780)
whereas Cks1 knockdown led to a decrease in colony
formation in estrogen-containing medium [110].
We have also shown that Cks1 depletion in MCF-7
breast cancer cells blocks cell cycle progression induced
by both estrogen dependent and growth factor dependent
pathways [70]. Cks1 depletion not only slows progres-
sion through G1-S, but also blocked their entry into M
phase. Cks1 silencing also leads to a rapid loss of Skp2,
concomitant increases in p130/Rb2 and p27Kip1, and
marked reduction in the level of CDK1, which is essen-
tial for M phase entry. Interestingly Cks1 loss does not
alter cell cycle profiles in human mammary epithelial
cells or normal human lung fibroblast suggesting that
targeting it might provide selectivity [70].
Given its importance in cancer progression it is not
surprising that significant efforts have been directed to
target Cks1 as a potential anti cancer target. Fluoxetine
and Vorinostat are two drug candidates that have been
shown to induce an accumulation of p27Kip1 and p21Cip1
and consequently cause cell cycle arrest through a Cks1
dependent mechanism in MDA-MB-231 breast cancer
cells [84,116]. A DNA-microarray analysis to evaluate
the anticancer effects of a dietary supplement Myco-
Phyto® Complex (MC) has revealed that MC inhibits
expression of Cks1 in MDA-MB-231 breast cancer cells
suggesting a potential role for Cks1 targeting by chemo-
preventives [117]. An in silico screen targeting the phos-
pho-p27Kip1 binding pocket led to development of a fam-
ily four specific small molecule inhibitors collectively
referred to as SKPins (C1, C2, C16, and C20) that pre-
vent the ubiquitination and degradation of p27Kip1 and
p21Cip1 exclusively by perturbing critical interactions that
allow phospho-p27Kip1 to bind in the pocket formed by
Skp2-Cks1 [118-120]. This ultimately ensues in a cell
type specific block in G1 or G2/M phase in T47D and
MCF-7 respectively. Not surprisingly mutations in key
residues mediating these contacts (for instance Cks1
Q52L) can reverse the inhibitory activity of some these
compounds [120].
4.2. Cks1 in Other Malignancies
Expression analyses utilizing microarray platforms, qPCR
studies and IHC analyses have revealed that Cks1 is
overexpressed in different subtypes of lymphoma in-
cluding mantle cell lymphoma (MCL) and mantle cell
lymphoma blastoid variant (MCL-BV), and contributes to
development of disease and resistance to cancer chemo-
therapy [121-124]. Studies delineating the precise me-
chanisms of Cks1 role in development and progression of
lymphomas are still lacking however an important study
in this regard has shown that Myc induced Cks1 can drive
development of disease [81]. Loss of Cks1 markedly
delays lymphoma development and dissemination of
disease in the Eµ-Myc transgenic mouse lymphoma mo-
del [81]. Furthermore inhibition of PI3K/Akt pathways
can decrease MCL growth by inducing p27Kip1 accumu-
lation through Cks1 and Skp2 downregulation [17]. In yet
another report it was found that retinoic acid downregu-
lates the expression of the Cks1 and Skp2 proteins thus
slowing down p27Kip1 degradation in lymphoblastoid B
cell lines [125].
Expression studies have employed fluorescent in situ
hybridization and other methods to ascertain prevalence
and prognostic significance of Cks1 gain following 1q21
amplification in multiple myeloma (MM) progression
[126-129]. Cks1 gain is associated with transformation
from benign monoclonal gammopathy of undetermined
significance (MGUS) to more aggressive forms MM and
plasma cell leukemias (PCL) and a shorter disease free
survival [127]. Like lymphoma, little is known about
detailed mechanisms of Cks1 in MM cells. However a
study utilizing microarray based gene expression analysis
of CD138 enriched plasma cells from MM patients un-
dergoing melphalan based high dose therapy has sug-
gested Skp2 and p27Kip1-dependent and independent
mechanisms that fuel into multiple myeloma progression
Copyright © 2013 SciRes. JCT
Cks1: Structure, Emerging Roles and Implications in Multiple Cancers
[130]. In fact Cks1 overexpression leads to multidrug
resistance in multiple myeloma and stimulates STAT3
and MEK/ERK signaling pathways [21].
Cks1 is also highly overexpressed in the majority of
different cancer subtypes afflicting the gastrointestinal
system and in most cases is strongly correlated to in-
creased Skp2 expression and reduced p27Kip1 expression.
Cks1 has been implicated in development of oral squa-
mous cell carcinoma [131-133], salivary gland tumors
[106], esophageal carcinomas [80,134,135], gastric car-
cinoma [20,136], colorectal carcinoma [108], gall blad-
der carcinoma [137] and hepatocellular carcinoma [19,
138-142]. Similarly Cks1 is believed to play a role in
development and progression of several other types of
cancers such as endometrial cancer [143], ovarian tumors
[144-147], prostate cancer [148], testicular cancer [149],
non small cell lung carcinomas (NSCLC) [111,150], cu-
taneous squamous cell carcinoma [151], melanoma [15],
urothelial carcinoma and renal cell carcinomas [152,153],
glioblastoma and CNS tumors [154,155], head and neck
carcinoma [156], fibrosarcoma [157], and myxofibrosar-
coma [158]. In many of these studies there is often a dis-
tinct correlation between Cks1 expression and clinicopa-
thologic features such as tumor grade, stage, metastasis,
loss of tumor differentiation patient prognosis and cancer
free survival.
5. Conclusion
In conclusion, cellular and biochemical studies providing
a clearer understanding of Cks1 and its function in cancer
biology is likely to yield attractive avenues for therapeu-
tic intervention.
6. Acknowledgements
Work in the authors’ laboratory was supported by grants
from the Komen Breast Cancer Foundation grant
(BCTR00-456), IR&D grant 1094, NCI Breast SPORE
Developmental grant, Adolph Weil Endowment Fund
and NIH (CA50376).
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