The International Journal of Biochemistry & Cell Biology 68 (2015) 914

Contents lists available at ScienceDirect

The International Journal of Biochemistry

& Cell Biology
journal homepage: www.elsevier.com/locate/biocel

Signalling networks in focus

p27Kip1 signaling: Transcriptional and post-translational regulation

Su Su Thae Hnit a , Chanlu Xie a , Mu Yao b , Jeff Holst c,d , Alan Bensoussan e , Paul De Souza f ,
Zhong Li g, , Qihan Dong a,b,f,
a

School of Science and Health, University of Western Sydney, Australia

Central Clinical School and Charles Perkins Centre, The University of Sydney and Department of Endocrinology, Royal Prince Alfred Hospital, Sydney,
Australia
c
Origins of Cancer Program, Centenary Institute, Camperdown, NSW, Australia
d
Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
e
National Institute of Complementary Medicine, University of Western Sydney, Australia
f
School of Medicine, University of Western Sydney, Australia
g
Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
b

a r t i c l e

i n f o

Article history:
Received 17 April 2015
Received in revised form 8 August 2015
Accepted 10 August 2015
Available online 14 August 2015
Keywords:
p27Kip1
MYC
SKP2
KPC
CRM1
PIRH2

a b s t r a c t
p27Kip1 is an inhibitor of a broad spectrum of cyclin-dependent kinases (CDKs), and the loss of a single
p27Kip1 allele is thereby sufcient to increase tumor incidence via CDK-mediated cell cycle entry. As such,
down-regulation of p27Kip1 protein levels, in particular nuclear expressed p27Kip1 , is implicated in both
disease progression and poor prognosis in a variety of cancers. p27Kip1 expression is positively regulated
by the transcription factor MENIN, and inhibited by oncogenic transcription factors MYC and PIM. However, regulation of p27Kip1 protein expression and function is predominantly through post-translational
modications that alter both the cellular localization and the extent of E3 ubiquitin ligase-mediated
degradation. Phosphorylation of p27Kip1 at Thr187 and Ser10 is a prerequisite for its degradation via the E3
ubiquitin ligases SKP2 (nuclear) and KPC (cytoplasmic), respectively. Additionally, Ser10 phosphorylated
p27Kip1 is predominantly localized in the cytoplasm due to the nuclear export protein CRM1. Another E3
ubiquitin ligase, PIRH2, degrades p27Kip1 in both the cytoplasm and nucleus independent of phosphorylation state. As such, inhibition of cell cycle entry and progression in a variety of cancers may be achieved
with therapies designed to correct p27Kip1 localization and/or block its degradation.
2015 Elsevier Ltd. All rights reserved.

1. Introduction

Abbreviations: ABL, abelson murine leukemia viral oncogene homolog; AKT,

protein kinase B; Ala, alanine; AMPK, 5 adenosine monophosphate-activated protein kinase; ATP, adenosine triphosphate; E2F, elongation 2 transcription factor;
FOXO3a, forkhead box O3a; JAK2, janus kinase 2; kDa, kilodalton; KIS, kinase interacting stathmin; LYN, lck/yes-related novel protein tyrosine kinase; MAT1, menage
a trois 1-CDK-activating kinase assembly factor; MAX, myc-associated factor X;
miR, microRNA; MYC, v-myc avian myelocytomatosis viral oncogene homolog;
p21Cip1 , CDK-interacting protein 1; p27Kip1 , cyclin dependent kinase inhibitor 1B;
PIM, proto-oncogene serine/threonine-protein kinase; PIRH2, p53-induced protein
with a RING-H2 domain; RB, retinoblastoma; RING nger domain, really interesting new gene nger domain; SCF, Skp1-Cullin-Fox complex; Ser, serine; SGK,
serum/glucocorticoid-regulated kinase; siRNA, small interference RNA; SKP2, sphase kinase-associated protein 2; SRC, proto-oncogene tyrosine-protein kinase
SRC; TGF, transforming growth factor ; Thr, threonine; Tyr, tyrosine.
Corresponding author at: School of Science and Health, The University of Western Sydney, Penrith South, NSW 2751, Australia.
Corresponding author at: Dongzhimen Hospital, Beijing University of Chinese
Medicine, 5 Haiyuncang Hutong, Dongcheng, Beijing, China.
E-mail addresses: lee171@163.com (Z. Li), q.dong@uws.edu.au (Q. Dong).
http://dx.doi.org/10.1016/j.biocel.2015.08.005
1357-2725/ 2015 Elsevier Ltd. All rights reserved.

In 1994, a 27 kDa protein was found to inhibit the activity of

the cyclin-dependent kinase 2 (CDK2) following treatment of mink
lung epithelial cells with TGF (Polyak et al., 1994). This protein was named CDK inhibitor 1B or p27. As a member of kinase
inhibitor protein (KIP) family, p27 was subsequently named as
p27Kip1 and was thought to control cell cycle progression in G1
phase (Polyak et al., 1994). While this has been conrmed by other
groups (Grimmler et al., 2007; OHagan et al., 2000; Sheaff et al.,
1997), p27Kip1 can also bind and inhibit cyclin-CDK complexes
beyond the G1 phase of cell cycle (James et al., 2008).
p27Kip1 is haploinsufcient, with the loss of a single p27Kip1
allele being sufcient to increase tumor incidence (Gao et al., 2004).
Decreased levels of p27Kip1 protein, in particular nuclear expressed
p27Kip1 , is implicated in disease progression and poor prognosis
in lung, head and neck, colon, breast, ovary and prostate cancer
(Chu et al., 2008). p27Kip1 -null mice show multiorgan hyperplasia,
retinal dysplasia, increased body size and tumor formation (Fero
et al., 1996; Gao et al., 2004), suggesting an indispensable function

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of p27Kip1 . Hence, understanding the regulation of p27Kip1 expression via both transcriptional and post-translational mechanisms is
of clinical importance.
2. Functions of p27Kip1
The p27Kip1 gene is located on chromosome 12p13 (Pietenpol
et al., 1995). The CDK-inhibitory domain resides in the N-terminal
portion of p27Kip1 and is sufcient to arrest cells at G0 /G1 . The Cterminal portion of p27Kip1 is less conserved in the KIP family and
contains a nuclear localization signal (Polyak et al., 1994; Russo
et al., 1996).
2.1. Inhibitor of cyclin E/A-CDK2
The role of p27Kip1 in blocking cyclin E/A-CDK2 is well characterized. p27Kip1 interacts with cyclin A through a conserved cyclin
binding domain, and CDK2 via the kinase binding region (Russo
et al., 1996). p27Kip1 inhibits cyclin E/A-CDK2 activity by three distinct mechanisms: (i) blocking ATP access to CDK (ii) preventing
substrate access to the CDK, and (iii) preventing the activating
phosphorylation of CDK by the CDK-activating kinase (i.e. cyclin
H/CDK7/MAT1). As a result, the cyclin E/A-CDK2 complex is unable
to phosphorylate RB, causing a pause in the transcription of genes
required for progression to S phase. Furthermore, this results in
inhibition of other S-phase promoting activities such as formation
of the origin recognition complex for DNA replication through the
cyclin E/A-CDK2 complex (Aleem et al., 2005; James et al., 2008;
Ray et al., 2009; Russo et al., 1996).
2.2. The mode of action on cyclin D-CDK4/6
The relationship of p27Kip1 and cyclin D-CDK4/6 is complex (Ray
et al., 2009). p27Kip1 -bound cyclin D-CDK4/6 complexes remain
catalytically active in proliferating keratinocytes, epithelial or lymphoid cells (James et al., 2008). In quiescent epithelial and resting
lymphoid cells, however, p27Kip1 -bound cyclin D-CDK4/6 complexes are inactive. It is believed that the effect of p27Kip1 on the
activity of cyclin D-CDK4/6 is dependent on the growth state of
the cells (James et al., 2008; Ray et al., 2009). In cycling cells,
the p27Kip1 -cyclin D-CDK4/6 complex is active due to the phosphorylation at Tyr74 , Tyr88 and/or Tyr89 (Ray et al., 2009). The
phosphorylation of p27Kip1 pushes its tail out of the catalytic cleft
of CDK4/6, exposing the CDK4/6 active site to ATP and substrate. In
non-cycling cells, Tyr88 and Tyr89 are not phosphorylated, resulting in occupation of catalytic cleft of the CDK by p27Kip1 tail (Ray
et al., 2009), i.e., the bound and inhibitory mode of p27Kip1 . By
blocking cyclin D-CDK4/6 complexes from phosphorylating RB, and
consequent repression of the transcription activity of E2F, the transcription of the genes required for G1 -S transition is halted.

Apart from controlling proliferation, p27Kip1 has also been

shown to have a role in differentiation, affecting terminal differentiation of neuronal stem cells (Bahrami et al., 2005) and erythroid
differentiation of a multipotent human leukemia cell line (MunozAlonso et al., 2005). Furthermore, cytoplasmic p27kip1 promotes
cell migration and metastasis in HepG2 hepatocellular carcinoma
cells (Denicourt and Dowdy, 2004; McAllister et al., 2003).
3. Transcriptional and post-translational regulation of
p27Kip1 by MYC, FOXO, PIM and MENIN
MYC is an oncogenic transcription factor of the
helixloophelix/leucine zipper family. The human MYC gene
family is composed of MYC, MYCN and MYCL1, and all three
MYC gene products have similar effects on cell cycle progression
(Bretones et al., 2015). MYC-MAX heterodimer binds to E-boxes in
the regulatory regions of its targeted genes and recruits transcriptional coactivators or repressors. Transient overexpression of MYC
in Jurkat T cells and breast cancer cells increased binding of the
MYC homology box II to the p27Kip1 promoter, directly repressing
p27Kip1 gene transcription (Yang et al., 2001). By comparison,
Forkhead box O proteins (FOXO4, FOXO3a, and FOXO1a) are
transcription factors that can induce p27Kip1 gene expression,
leading to cell cycle arrest at G0 /G1 (Fig. 1). Interestingly, MYC
can also suppress p27Kip1 transcription through an interaction
between the MYC homology box II domain and the DNA-binding
portion of FOXO3a in mouse broblasts, breast cancer cells, Jurkat
T cells and human embryonic kidney cells (Bretones et al., 2015;
Chandramohan et al., 2008).
Another mechanism by which MYC regulates p27Kip1 expression
is through transcriptional regulation of other genes and microRNAs. MYC transcriptionally regulates expression of miR-221 and
miR-222, which have been shown to target p27Kip1 mRNA in
glioblastoma cell lines (le Sage et al., 2007; Pineau et al., 2010).
MYC also regulates expression of E3 ubiquitin ligase components
SKP2 and CUL1, leading to p27Kip1 protein degradation (Bretones
et al., 2011; OHagan et al., 2000). Other MYC target genes, such as
E2F (E2F1, E2F2 and E2F3) transcription factors, may also play a role
in regulating p27Kip1 , by inducing cyclin E expression (Muller et al.,
1997; Prez-Roger et al., 1997) (Fig. 1).
The serine/threonine kinase PIM family members (PIM1, PIM2
and PIM3) have been shown to directly phosphorylate p27Kip1 at
Thr157 and Thr198 , resulting in cytoplasmic localization (Morishita
et al., 2008). Furthermore, PIM1S (PIM1 short isoform) can phosphorylate and inactivate FOXO3a at Thr32 and Ser253 and FOXO1a at
Thr24 , Ser256 and Ser319 , thereby repressing FOXO-mediated p27Kip1
gene transcription in human embryonic kidney cells (Morishita
et al., 2008). MENIN is encoded by the MEN1 gene, and its mutation
is responsible for multiple endocrine neoplasia type 1. MENIN binds
to the p27Kip1 gene promoter and activates p27Kip1 gene expression
by modulating histone methyltransferase activity (Chu et al., 2008;
Karnik et al., 2005) (Fig. 1).

2.3. Inhibitor of cyclin B-CDK1

Studies in mice have demonstrated that knockout of CDK2, CDK3,
CDK4 and CDK6 are not lethal (Adhikari et al., 2012; Santamaria
et al., 2007). Mouse oocytes lacking these interphase CDKs are still
able to proliferate, revealing that CDK1 can replace these interphase CDKs and drive cell division (Adhikari et al., 2012; Santamaria
et al., 2007). In CDK2 knockout mice, p27Kip1 was found to bind and
inhibit CDK1 activity in the thymus and spleen (Aleem et al., 2005).
Deletion of p27Kip1 signicantly upregulated CDK1 activity and promoted G1 -S transition (Aleem et al., 2005). The exact mechanism
underlying p27Kip1 regulation of G1 -S transition through CDK1 is
yet to be determined.

4. Phosphorylation of p27Kip1 at Thr187 promotes

SCFSKP2 -dependent degradation in the nucleus
Despite these clear transcriptional mechanisms, regulation of
p27Kip1 is mainly via post-translational modications. The protein
level of p27Kip1 is controlled by ubiquitin-dependent proteolysis,
which requires phosphorylation of p27Kip1 (Chu et al., 2008). The
phosphorylation of p27Kip1 at Thr187 by cyclin E-CDK2 is recognized
by the F-box protein SKP2, a subunit of the SCF E3 ubiquitin ligase (SCFSKP2 ), and thus triggers ubiquitin-dependent degradation
in the nucleus (Fig. 2A). The importance of Thr187 phosphorylation is demonstrated by introduction of the Ala187 mutation, which

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11

Fig. 1. Transcriptional and post-translational regulation of p27Kip1 by MYC, PIM and MENIN. MYC represses the transcription of p27Kip1 gene (CDKN1B) directly or indirectly
via inactivating FOXO3a-mediated CDKN1B transcription. MYC induces miR-221 and miR-222, which can silence p27Kip1 mRNA. MYC also induces cyclin E gene (CCNE1)
transcription directly or indirectly through E2F transcription factors. MYC also upregulates SKP2 transcription and the increased SKP2 levels contribute to degradation of
p27Kip1 protein by SCFSKP2 -mediated ubiquitination. PIM suppresses p27Kip1 gene expression by inactivating FOXO1a and FOXO3a by phosphorylation. MENIN can directly
bind to the p27Kip1 promoter and induce p27Kip1 gene expression.

leads to resistance to degradation of p27Kip1 and G1 arrest in

mouse broblasts (Sheaff et al., 1997). Similar mutation of Thr187
to Gly187 also increased p27Kip1 stability in the extracts of HeLa
cells (Tsvetkov et al., 1999). As p27Kip1 binds the cyclin E/A-CDK2
complex, p27Kip1 is also a substrate of the complex (Sheaff et al.,
1997). The progressive decrease of p27Kip1 in G1 permits cyclin
E/A-CDK2 to promote the G1 -S transition in HeLa cells (Tsvetkov
et al., 1999). Despite clear evidence that degradation of p27Kip1 by
SCFSKP2 occurs during S phase (Tsvetkov et al., 1999), there are suggestions that SCFSKP2 may also degrade p27Kip1 in other cell cycle
phases (Chu et al., 2008; Hattori et al., 2007; Kamura et al., 2004).
There is also an accessory protein, cyclin-dependent kinases regulatory subunit 1 (CKS1), which appears to be necessary to bridge
between p27Kip1 and SCFSKP2 as determined by the 3D structure of
the ternary complex (Hao et al., 2005).
There is also evidence to support SCFSKP2 -mediated proteolysis
independent of Thr187 phosphorylation, working together with
a subunit of the damaged-DNA binding protein (DDB1), CUL4A
(Cullin 4A) and the COP9 signalosome (Bondar et al., 2006).
siRNA-mediated knockdown of DDB1, CUL4A, and CSN1 (a subunit
of the signalosome) causes an accumulation of p27Kip1 , whereas
overexpression of DDB1 reduces the level of p27Kip1 in HeLa cells
(Bondar et al., 2006). Further studies are needed to verify this form
of p27Kip1 regulation.
5. Phosphorylation of p27Kip1 at Ser10 fosters
KPC-dependent degradation in the cytoplasm
By analyzing crude extracts of SCFSKP2 knockout cells, the SKP2
independent E3 ubiquitin ligases Kip1 ubiquitylation-promoting
complex (KPC), containing KPC1 and KPC2, were found in the
cytoplasmic fraction of the rabbit reticulocyte sample (Chu et al.,
2008; Kamura et al., 2004). Through binding to CDK interacting
site of p27Kip1 (Kotoshiba et al., 2005), KPC1 and KPC2 mediate
the cytoplasmic p27Kip1 ubiquitination in G1 -S phase in a Ser10

phosphorylation-dependent manner (Fig. 2B). Overexpression of

both KPC1 and KPC2 stimulated the degradation of p27Kip1 while
the ubiquitination of p27Kip1 was reduced with a loss-of-function
mutation in KPC1 in mouse broblasts. Moreover, the treatment of
NIH 3T3 cells with KPC1 RNAi induced a delay in p27Kip1 degradation, with a similar effect observed in mouse embryonic broblasts
resulting in a decrease of p27Kip1 degradation in G0 -G1 transition
(Kamura et al., 2004). This study demonstrated that the action of
KPC regulates p27Kip1 degradation in G0 to S phase (Kamura et al.,
2004) and therefore further studies are required to examine its
action on G2 and M phase in the presence of active SKP2.
6. Phosphorylation at Ser10 stimulates nuclear export of
p27Kip1 by CRM1
As an inhibitor of DNA duplication and cell division, p27Kip1
exerts its anti-proliferative action inside the nucleus. Chromosome
region maintenance 1 (CRM1) is a carrier protein for nuclear export
(Wang et al., 2013), which mediates the cytoplasmic translocation
of p27Kip1 through binding to its CDK interacting site (Chu et al.,
2008). In early G1 , phosphorylation of p27Kip1 at Ser10 by kinases
including AKT, CDK5 and KIS facilitates its binding to CRM1 and
subsequent transport from the nucleus to the cytoplasm (Fig. 2B).
Mutation of Ser10 to Ala10 reduces p27Kip1 nuclear export, and led
to accumulation of p27Kip1 in the nucleus of mouse broblasts even
after serum stimulation (Ishida et al., 2002). In CRM1 siRNA treated
ovarian cancer cells, a reduction of CRM1 protein levels and coincident accumulation of Ser10 phosphorylated p27Kip1 in the nuclear
fraction were observed (Wang et al., 2013). These data suggest
that CRM1 plays an essential role in the subcellular localization
of p27Kip1 and subsequently in cell cycle regulation. Since Ser10
phosphorylation promotes KPC-dependent degradation in the
cytoplasm, it is possible that KPC-mediated degradation of p27Kip1
in G1 phase requires CRM1 to export p27Kip1 from the nucleus.

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Fig. 2. Regulation of p27Kip1 activity, stability and sub-cellular localization by phosphorylation. (A) Phosphorylation of p27Kip1 at Thr187 by cyclin E-CDK2 in the nucleus
promotes SCFSKP2 -dependent ubiquitination and subsequent degradation. (B) Phosphorylation of p27Kip1 at Ser10 in early G1 allows CRM1-dependent export of nuclear p27Kip1
to the cytoplasm. The cytoplasmic Ser10 phosphorylated p27Kip1 undergoes KPC-mediated ubiquitination and subsequent degradation. (C) Phosphorylation of p27Kip1 at Tyr74,
88, 89
by mitogenic kinases displaces the inhibitory helix from the catalytic cleft of CDK, thereby restoring the cyclin-CDK catalytic activity, while p27Kip1 remains bound to
cyclin-CDK complexes. (D) Thr157 or Thr198 phosphorylation forms the recognition motif for 14-3-3 proteins, which can bind and sequester p27Kip1 in the cytoplasm.

7. Phosphorylation at Tyr74 , Tyr88 and/or Tyr89 diminishes

CDK-inhibitory activity of p27Kip1
Tyr74 , Tyr88 and Tyr89 are located in the CDK binding domain of
p27Kip1 . A phosphorylation of any of these tyrosine residues during the G0 -G1 transition decreased its CDK-inhibitory activity by
pushing the p27Kip1 tail away from the catalytic cleft of CDK4/6,
providing access for both ATP and substrate at the CDK catalytic
cleft (Jkel et al., 2012; Russo et al., 1996) (Fig. 2C). The phosphorylation at Tyr74 , Tyr88 and Tyr89 is achieved by non-receptor tyrosine
kinases like ABL, SRC and LYN in breast cancer cells (Grimmler
et al., 2007) and the receptor tyrosine kinase JAK2 in patient derived
erythroleukemia cells. Tyr88 is preferentially phosphorylated (Jkel
et al., 2011). Since Tyr phosphorylation by SRC facilitates CDK2
to phosphorylate p27Kip1 at Thr187 , resulting SCFSKP2 -dependent
degradation at S phase, SRC promotes proteolysis of p27Kip1 both
prior to and at S phase (Chu et al., 2007; Grimmler et al., 2007).
8. Phosphorylation of Thr157 and Thr198 impairs nuclear
import resulting cytoplasmic localization
Nuclear import of p27Kip1 is also regulated by phosphorylation, with Thr157 and Thr198 phosphorylation preventing nuclear
import, resulting in cytoplasmic localization of p27Kip1 . Compared
to phosphorylation on Ser10 , which stimulates nuclear export
of p27Kip1 by CRM1, Thr157 and Thr198 phosphorylation is less

common and is induced by serum stimulation (Jkel et al., 2012). In

early G1 phase, phosphorylation at Thr157 and Thr198 by AKT, p90
ribosomal protein S6 kinases, serum and glucocorticoid-inducible
kinase (SGK), AMPK and PIM (Morishita et al., 2008) cause a delay
in nuclear import of p27Kip1 (Fig. 2D). Phosphorylation of Thr157
and Thr198 by AKT can form a recognition motif for 14-3-3 proteins
to sequester p27Kip1 in the cytosol of HeLa and human embryonic
kidney cells (Sekimoto et al., 2004). In addition, since Thr157 is
within the nuclear localization signal of p27Kip1 (Sekimoto et al.,
2004), it has been proposed that Thr157 phosphorylation may
interfere with p27Kip1 nuclear import (Sekimoto et al., 2004).

9. Phosphorylation-independent degradation of p27Kip1 by

PIRH2 in the nucleus and cytoplasm
p53-induced RING-H2-type ubiquitin ligase (PIRH2) is a
p27Kip1 -interacting protein. PIRH2 degrades p27Kip1 in G1 phase
independent of phosphorylation state in both the nucleus and cytoplasm (Hattori et al., 2007). PIRH2 interacts with p27Kip1 through
the RING nger domain (Hattori et al., 2007). The expression of
PIRH2 is low in G0 , but is induced in late G1 to S phase in human
glioblastoma (T98G) cells (Hattori et al., 2007). Knockdown of
PIRH2 thereby prevented the cell cycle re-entry of serum-starved
cells following the restoration of serum (Hattori et al., 2007).

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Hence, PIRH2 is another negative regulator of p27Kip1 via ubiquitindependent proteasomal degradation.
10. Associated pathologies and therapeutic implication
Low protein levels or cytoplasmic expression of p27Kip1 is associated with cancer aggressiveness and poor clinical prognosis (Chu
et al., 2008). The main cause of low p27Kip1 expression in cancer is
unlikely via mutations or epigenetic silencing, but rather through
aberrant p27Kip1 degradation, repressed p27Kip1 expression, and
increased cytoplasmic localization (Chu et al., 2008). High levels
of SKP2, KPC and PIRH2 together with low levels of p27Kip1 were
shown in many human cancers, suggesting that accelerated degradation of p27Kip1 by E3 complexes is involved in carcinogenesis and
progression (Bretones et al., 2011; Chu et al., 2008; Huang et al.,
2011; Kamura et al., 2004). In the presence of MYC, low levels of
p27Kip1 result in tumor formation in animals (Bretones et al., 2011).
High level of MYC also inhibit FOXO-mediated p27Kip1 expression
in many tumor cells (Chandramohan et al., 2008). miRNA-221 and
miRNA-222 are frequently upregulated in tumor tissues, and correlate with low levels of p27Kip1 in cancers (le Sage et al., 2007;
Pineau et al., 2010). Finally, cytoplasmic localization of p27Kip1 also
occurs in cancers (Sekimoto et al., 2004). Since the nuclear export of
p27Kip1 is regulated by SRC (Chu et al., 2007) and CRM1 (Wang et al.,
2013), while the cytoplasmic-nuclear shuttling is blocked by PIM
(Morishita et al., 2008) and 14-3-3 proteins (Sekimoto et al., 2004),
the increased levels of SRC, CRM1 and PIM in many cancers could
contribute to p27Kip1 cytoplasmic localization (Chu et al., 2007;
Morishita et al., 2008; Wang et al., 2013). Indeed, CRM1-positive
expression in ovarian cancer was associated with higher tumor
grade and lymph node metastases (Wang et al., 2013). Patients
with high Ser10 phosphorylated p27Kip1 had signicantly shorter
survival time (Wang et al., 2013).
Since stability of p27Kip1 protein is a function of site specic phosphorylation, a strategy targeting the key phosphorylation
sites responsible for ubiquitination-mediated p27Kip1 degradation
should be considered. Benzoquinone ansamycin 17-allylamino geldanamycin (17-AAG) is a proteasome inhibitor that is able to
stabilize p27Kip1 by depletion of Cks1, the bridge between SKP2
and p27Kip1 (Khattar et al., 2014). Treatment of colon carcinoma
cells with 17-AAG resulted in G1 cell cycle arrest (Khattar et al.,
2014). Restoring p27Kip1 levels by inuencing its gene expression
regulators and rectifying p27Kip1 mislocalization via targeting SRC,
CRM1 and PIM, may also provide new avenue for treatment of a
variety of cancers.
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