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Cell cycle, proteolysis and cancer
Lili Yamasaki1 and Michele Pagano2
Research in the past 15 years has shown that the mammalian
cell cycle is controlled by the action of cyclin-dependent
kinases (CDKs). A crucial substrate of the CDKs in G1-phase is
the retinoblastoma tumor suppressor (pRB), which restrains
proliferation largely by repressing the activity of the E2F
transcription factors. More recent work has shown that
the cell cycle is also a tale of two classes of ubiquitin ligases,
referred to as SCF and APC/C ligases. CDKs, E2F and ubiquitin
ligases reciprocally regulate each other, resulting in complex
feedback loops. Perturbation of this network of molecular
machines is associated with proliferative diseases,
including cancer.
Addresses
1
Biological Sciences, Columbia University, New York, USA
e-mail: [email protected]
2
Department of Pathology and NYU Cancer Institute, New York
University School of Medicine, New York 10016, USA
e-mail: [email protected]
Current Opinion in Cell Biology 2004, 16:623–628
This review comes from a themed issue on
Cell division, growth and death
Edited by Steve Reed and Joel Rothman
Available online 28th August 2004
0955-0674/$ – see front matter
# 2004 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.ceb.2004.08.005
Abbreviations
APC/C anaphase promoting complex/cyclosome
CDK
cyclin dependent kinase
Emi1
early mitotic inhibitor 1
FBP
F-box protein
Fbw7
F-box, WD40 domain containing protein 7
pRB
retinoblastoma tumor suppressor
SCF
Skp1-Cul1-F-box protein complex
Skp2
S-phase kinase associated protein 2
Introduction
Our global view of how changes in cell cycle regulators
facilitate the development of cancer is based heavily on
the spectrum of mutations found in human tumors, which
alter the expression or activity of these regulators, and on
the changes in cell cycle properties of cultured cells and
phenotypes of transgenic mice engineered to express
these regulators. Certainly, gain-of-function mutations
that result in the overexpression of positive regulators
of G1-phase or the G1/S-transition, such as D-type or Etype cyclins, are found frequently in human tumors and
correlate with a poor prognosis of survival [1]. Similarly,
loss or decreased expression of the INK4 or CIP/KIP
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family of cyclin-dependent kinase (CDK) inhibitors is
often found in human tumors. Mutations at Chr9p21
frequently occur in human tumors that inactivate INK4A
(and at the same time ARF, an overlapping gene that
encodes a stabilizer of the p53 tumor suppressor) and
INK4B [2], and the decreased expression of KIP1, encoding p27, is commonly found in human tumors and also
correlates with a poor prognosis [3]. Studies in cultured
cells have demonstrated that the decreased expression of
p27 or the overexpression of D-type or E-type cyclins
causes a shortening of the G1-phase and contributes to
transformation as evaluated by growth in soft agar and
focus formation assays. Mice lacking p27 develop adenomas of the intermediate lobe of the pituitary and the
overgrowth of multiple organs (reviewed in [3]). Mice
expressing Cyclin D1 in the mammary epithelium
develop mammary hyperplasia and mammary carcinomas
at low penetrance [4], while mice lacking Cyclin D1
(Ccnd1 / ) are resistant to breast tumors induced by
the neu or Ras oncogenes [5].
G1 cyclin–CDK complexes phosphorylate the retinoblastoma tumor suppressor (pRb), thereby inactivating its
growth suppressive function (mostly due to the inhibition
of E2Fs, factors inducing the transcription of genes
involved in the G1/S transition). In fact, 50% of human
tumors contain loss-of-function mutations in RB [2,6].
Mutations in RB itself or in the upstream regulators of RB
(e.g. INK4A, CCND1) are found in a mutually exclusive
pattern in virtually all human tumors, giving rise to the
model that the RB tumor suppressor pathway forms a
major barrier to proliferation that tumor cells must overcome during neoplastic progression.
Whereas the role of abnormal cell cycle regulation in
cancer due to genetic alterations (deletions of cell cycle
inhibitors such as RB, or activation of cell cycle inducers
such as Cyclin D1) is well established, there is increasing
evidence that aberrant destruction of cell cycle regulatory
proteins also contributes significantly to oncogenic transformation [7]. We will review some recent published
evidence showing that deregulation of cell cycle regulatory ubiquitin ligase enzymes plays a role in cancer
development.
Deregulation of SCF and APC/C ubiquitin
ligases in cancer
Fast, specific and timely proteolysis of cell cycle regulators by the ubiquitin-proteasome system represents an
important mechanism that ensures proper progression
through the cell division cycle in a unidirectional and
irreversible manner. The large number of ubiquitin
Current Opinion in Cell Biology 2004, 16:623–628
624 Cell division, growth and death
ligases (>500 in mammals) provides the high level of
substrate specificity observed. Proteolysis of most core
components of the cell cycle machinery is controlled by
two major classes of ubiquitin ligases: the SCF (Skp1–
Cul1–F-box protein) complexes and the anaphase promoting complex/cyclosome (APC/C). In mammals, there
are >70 SCF ligases, each characterized by a different Fbox protein (FBP) subunit that provides specificity by
directly recruiting the substrate to the rest of the ligase
and ultimately to the ubiquitin conjugating enzyme [8].
The APC/C ligase comes in two forms: one activated by
Cdh1 (which contributes to keep CDK activities at low
levels and therefore to maintain the G0/G1 state) and
another activated by Cdc20 (necessary for progression
through mitosis and for inactivating Cdk1, thereby allowing the exit from mitosis) [9].
other SCF subunits. Not only does the SCF ligase control
APC/C, but the APC/C also regulates the SCF ligase.
During G1, APC/CCdh1 promotes the proteolysis of the
FBP Skp2 and its cofactor Cks1 (Figure 1), thus preventing the premature degradation of SCFSkp2 substrates,
including p27 [12,13], its major effector [14].
A simplified view of these interactions is illustrated in
Figure 1. Briefly, the activation of two major inducers of
cell proliferation, Cdk1 and Cdk2, is promoted by the
degradation of p27 through SCFSkp2. Skp2, in turn, is
degraded via APC/CCdh1, which is kept inactive by several mechanisms, including the interaction with Emi1,
which is ultimately eliminated through SCFbTrcp. This
linear axis shows that Skp2 and Emi1 are positive regulators of proliferation, whereas p27 and APC/CCdh1 are
negative regulators. In this model, bTrcp is an inhibitor of
cell proliferation too. However, while this is true in early
mitosis (when bTrcp promotes Emi1 proteolysis) [10,11]
and during most of interphase (when bTrcp induces
degradation of Cdc25a and other substrates) [15,16],
at G2/M bTrcp becomes an activator of Cdk1 by mediating the degradation of its inhibitory kinase Wee1 [17].
Furthermore, bTrcp has been implicated in the regulation of at least two additional proliferation-related signal
transduction pathways, Wnt/Wingless and NFkB, by
mediating the ubiquitylation and degradation of the
transcriptional co-activator b-catenin and the NFkB
inhibitor IkB, respectively [18].
Although it was believed that SCF ligases functioned
mainly at the G1/S transition, recent work has shown that
they are also active during other phases of the cell cycle.
For example, SCFbTrcp (conventionally, the FBP subunit
is superscripted after ‘SCF’ to indicate distinct SCF
complexes) mediates the degradation of the APC/C inhibitor Emi1 in pro-metaphase (Figure 1) [10,11], thus
contributing to the APC/C activation and the subsequent
progression to anaphase. By inhibiting APC/C during S
and G2 phases, Emi1 allows the accumulation of mitotic
cyclins, thereby contributing to the progression towards
mitosis. Although Emi1 itself is an FBP and can be
assembled in an SCF ligase complex, its substrates are
not currently known and its ability to inhibit APC/C
occurs via a physical interaction that does not require
A key difference between SCF and APC/C is in their
mode of substrate recognition. SCF complexes, in most
Figure 1
βTrcp
Fbw7
Emi1
Cyclin E
Notch1/4
Myc
Jun
APC/C
Skp2
p27
Cdk2
Cks1
Cell proliferation
Angiogenesis
Current Opinion in Cell Biology
Model showing the relationship between F-box proteins (bTrcp, Emi1, Skp2 and Fbw7), APC/C, CDKs and certain transcription factors
(Myc, Jun and Notch), and how this network regulates cell proliferation and angiogenesis. Recent data in the literature shows that inactivation
of Fbw7 and APC/C, and overexpression/overactivation of Emi1 and Skp2 might contribute to tumorigenesis. See text for details.
Current Opinion in Cell Biology 2004, 16:623–628
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Cell cycle, proteolysis and cancer Yamasaki and Pagano 625
cases, recognize substrates only when phosphorylated,
whereas APC/C recognizes specific motifs present in
the primary sequence of the substrate (e.g. Destruction
box, KEN box, etc.). Thus, SCF ligases ‘sense’ substrate
modifications by several kinases [8]. For example,
SCFbTrcp recognizes Emi1 only when Emi1 is phosphorylated by both Cdk1 and Plk1, and SCFSkp2 binds p27 only
if the latter is phosphorylated by CDKs. APC/C, on the
other hand, is regulated by phosphorylation, with APC/
CCdh1 being inhibited and APC/CCdc20 being activated by
CDKs. Thus, ubiquitin ligases and kinases form a complex network that includes numerous positive and negative feedback loops, which only recent studies are
beginning to elucidate.
Since SCF and APC/C ubiquitin ligases tightly control
CDK activity, it is expected that their deregulation may
play a major role in cancer. Many findings indicate that
Skp2 is an oncogene. First, Skp2 expression significantly
and directly correlates with tumor malignancy and aggressiveness and is associated with poor prognosis in breast
carcinomas, colorectal carcinomas, oral squamous cell
carcinomas, gastric carcinomas, prostate cancers, lymphomas and human astrocytic gliomas [3,18]. Similarly, Cks1
has been found to be highly expressed in gastric cancers
and oral squamous cell carcinomas [18]. Second, forced
expression of Skp2 in diploid fibroblasts induces DNA
synthesis in the absence of cell adhesion to the extracellular matrix [19,20]. Third, Skp2 cooperates with activated Ras in a focus formation assay and in inducing
growth in soft agar [19,21]. Fourth, cells overexpressing
Skp2 and activated Ras form tumors when injected into
nude mice [21]. Fifth, Skp2 cooperates with activated NRas in an in vivo model of lymphomagenesis [22]. Sixth,
targeted expression of Skp2 to the mouse prostate gland
induces the development of low-grade carcinomas [23].
In contrast to the large literature supporting a role for
Skp2 as an oncogene, only one study has evaluated the
possibility that APC/C could be a target of transforming
events. This report found that that two essential subunits
of APC/C, APC6/CDC16 and APC8/CDC23, often display
inactivating mutations in human colon cancer cells [24].
Inactivation of APC/CCdh1 during G1 could stabilize
substrates such as Skp2 and Cks1 and promote premature
S-phase entry, whereas inactivation of APC/CCdc20 in
mitosis may contribute to genomic instability by leading
to the accumulation of substrates such as Cyclin A,
Aurora-A, and Securin. This in turn could lead to aberrant
spindle formation and chromosomal segregation, which,
when not neutralized by apoptosis, may be a cause of
aneuploidy. Inactivation of APC/C may occur because of
mutations in certain subunits (both constitutive subunits
and activating subunits) but also because of an overexpression of Emi1. In fact, the levels of Emi1 transcript
and protein are often high in many human tumors,
particularly in breast, lung, colon, uterus and ovary
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[25]. Since Emi1 is an E2F target gene, it remains to
be seen whether this overexpression is simply due to the
deregulation of the E2F pathway commonly observed in
cancer, to amplifications in the EMI1 locus or to other
causes.
Theoretically, increased levels of Emi1 could derive from
an inactivation of SCFbTrcp activity. So far, however, only
very rare mutations in the BTRC and FBW1b genes (two
paralogous genes encoding bTrcp1 and bTrcp2, respectively) have been reported in human tumors [26–29],
probably because their pleiotropic activity against numerous substrates makes their inactivation incompatible with
a net growth advantage for the tumor cell. Loss of bTrcp1
in mouse results in a very low-incidence tumorigenesis in
the thymus and intestine [10], and does not cooperate in
transformation in vivo with the adenomatous polyposis
coli mutant Min/+ or with loss of p53 (D Guardavaccaro,
M Pagano and L Yamasaki, unpublished). By contrast,
several reports have shown that bTrcp1 and bTrcp2 are
overexpressed in cancer cell lines [30–32]. Accordingly, a
mouse model in which bTrcp1 is targeted to the mammary gland shows that overexpression of this FBP induces
hyperproliferation and activation of NFkB [33]. In addition, bTrcp1 can contribute to the transformation of the
mammary epithelium. No effects on proliferation and
transformation were observed when bTrcp1 expression
was targeted in lymphoid organs [33]. Thus, BTRC could
promote cell proliferation specifically in some tissues (e.g.
mammary gland), while in other tissues it could even
potentially suppress growth. It would be interesting to
identify the tissue-specific substrates in which increased
or decreased degradation is responsible for the differential properties of bTrcp1.
Another SCF ligase, SCFFbw7, is responsible for the
degradation of several oncoproteins, including c-Myc,
N-Myc, c-Jun, Cyclin E and Notch1/4 [18] (Figure 1).
These roles suggest that Fbw7 might function as a tumor
suppressor. In fact, mutations in FBW7 were found in
ovarian cancer cell lines and in 16% of primary endometrial adenocarcinomas, with loss-of-heterozygosity being
detected in most of these tumors [34,35,36,37]. Preliminary studies indicate that FBW7 mutations are often
associated with stabilization of its substrates and high
tumor aggressiveness.
Not only do p27, APC/CCdh1 and Fbw7 contribute to the
maintenance of the non-proliferative state but there is
strong evidence that they participate in inducing the
differentiation of certain tissues. This effect can be seen,
for example, in the mammalian brain where Fbw7 antagonizes Jun- (and perhaps Myc-) mediated apoptosis [38],
and where APC/C controls axonal growth and patterning
[39]. In addition, during neuronal differentiation, Skp2 is
downregulated with a consequent increase in p27 levels
[40–42]. Ectopic expression of a less-degradable Skp2
Current Opinion in Cell Biology 2004, 16:623–628
626 Cell division, growth and death
mutant, but not wild type Skp2, blocks neuronal
differentiation in cultured neurons (M Kirschner, unpublished result cited in [13]). This pathway may be targeted
in aggressive tumors, which are often characterized by
decreased differentiation. Significantly, low levels of p27
are predictive of poor prognosis in less differentiated
human neuroectodermal tumors [43–46].
A further growth advantage could be provided to the
neoplastic tissue by inhibiting the p27/APC/CCdh1/
Fbw7 network, since this seems to have a role in restraining angiogenesis: APC/CCdh1 and p27 do this by attenuating the cell proliferation that is necessary for endothelial
cells to grow, and Fbw7 does this more directly, by
antagonizing Jun-, Myc- and Notch-induced angiogenesis
[47–50] (Figure 1). A clear role for Fbw7 in angiogenesis
can be observed in Fbw7-deficient embryos that die
in utero at E10.5–11.5, with marked abnormalities in
vascular development in the brain and yolk sac [51,52].
There is also increasing evidence that Fbw7 might be
involved in controlling genomic instability [2,37]. Finally,
there is evidence that cytoplasmic p27 might promote cell
motility [53,54] and perhaps invasiveness. Therefore
nuclear p27 (bound to CDKs and in large part regulated
by Skp2) is a tumor suppressor, whereas cytoplasmic p27
(bound to RhoA and regulated by still unknown factors)
could be an oncoprotein. This would explain why the
KIP1 gene is rarely, if ever, lost in tumors.
Conclusions
The recent literature reviewed herein provides clear
evidence that deregulation of the ubiquitin ligases targeting cell cycle regulatory proteins contributes to tumorigenesis. This is achieved by two major mechanisms: either
overexpression of ubiquitin ligases whose substrates are
negative regulators of cell proliferation, or mutations of
ubiquitin ligases targeting tumor suppressor proteins. A
third important mechanism involves the substrate, which
can be stabilized by mutations that prevent its recognition
by the ubiquitin ligase. Overall, these aberrations decrease
the ability of the cell to make decisions about when and
whether to grow, proliferate or differentiate.
Can ubiquitin ligases be targeted for the therapy of
human tumors? Because they do not contain a canonical
active enzymatic site and their mode of action involves
protein–protein interactions, there is a concern that this
may be a hard nut to crack. However, a recent study has
shown that it is not impossible. Small molecule inhibitors
of Mdm2, the ligase for p53, have been identified by
screening a diverse library of synthetic chemicals [55].
These inhibitors, named Nutlins, bind Mdm2 in the p53binding pocket, thereby blocking the access of p53 and
resulting in its accumulation. Similarly, small molecule
inhibitors of SCF could be identified that block substrate
recognition. Alternatively, since a major function of the
SCF is to correctly orient and position the substrate to the
Current Opinion in Cell Biology 2004, 16:623–628
ubiquitin conjugating enzyme, allosteric inhibitors, or
even agonists, could be identified that just change the
angle at which the substrate is oriented without interfering with substrate binding.
Ubiquitin ligases and kinases both offer a very high level
of specificity. Despite differences in these two families of
enzymes, the challenge of targeting ubiquitin ligases is
reminiscent of that presented by kinases nearly 15 years
ago. The success with kinases, as well the recent use of
proteasome inhibitors in the clinic [7], will certainly spur
the development of therapies targeting ubiquitin ligases,
including those regulating the cell cycle.
Update
A recent paper [56] shows that bTrcp1 levels are
increased in 56% of 45 colorectal tumors analyzed and
that this overexpression associates with NFkB activation
and presence of metastasis. So, this study confirms previous ones indicating that bTrcp1 behaves as an oncoprotein in certain epithelial tissues.
Acknowledgements
We thank T Cardozo and L Gardner for critically reading this
manuscript, and we apologize to colleagues whose work could not be
mentioned due to space limitations. Work in the Yamasaki laboratory is
supported by a grant from the NIH (R01-CA79646), and in the Pagano
laboratory by grants from the NIH (R01-CA76584 and R01-GM57587).
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