Download p57 : “Kip”ing the Cell under Control

Published OnlineFirst November 24, 2009; DOI: 10.1158/1541-7786.MCR-09-0317
Subject Review
p57KIP2: “Kip”ing the Cell under Control
Ioannis S. Pateras, Kalliopi Apostolopoulou, Katerina Niforou,
Athanassios Kotsinas, and Vassilis G. Gorgoulis
Molecular Carcinogenesis Group, Laboratory of Histology-Embryology, Medical School,
University of Athens, Greece
Abstract
p57KIP2 is an imprinted gene located at the chromosomal
locus 11p15.5. It is a cyclin-dependent kinase inhibitor
belonging to the CIP/KIP family, which includes additionally
p21CIP1/WAF1 and p27KIP1. It is the least studied CIP/KIP
member and has a unique role in embryogenesis. p57KIP2
regulates the cell cycle, although novel functions have been
attributed to this protein including cytoskeletal organization.
Molecular analysis of animal models and patients with
Beckwith-Wiedemann Syndrome have shown its nodal
implication in the pathogenesis of this syndrome. p57KIP2 is
frequently down-regulated in many common human
malignancies through several mechanisms, denoting its
anti-oncogenic function. This review is a thorough analysis
of data available on p57KIP2, in relation to p21CIP1/WAF1 and
p27KIP1, on gene and protein structure, its transcriptional
and translational regulation, and its role in human
physiology and pathology, focusing on cancer development.
(Mol Cancer Res 2009;7(12):1902–19)
Introduction
Throughout the evolutionary process, cells have developed sophisticated molecular machinery in order to elicit, at any moment,
the proper decision with respect to cell fate. For this reason, external
and internal signals are continuously monitored, assimilated,
processed, and/or integrated, via complex biochemical-signaling
networks (1). At the heart of this complex, decision-making
molecular machinery, lies a cell nucleus-located core that resembles, in its operation, a clock apparatus (1). The determination of
the cell's fate toward proliferation, arrest, differentiation, quiescence, or apoptosis relies upon this cell clock (1).
The decision for cell cycle progression to occur, which is synonymous with proliferation, requires timely activation, followed by
subsequent ordered inactivation of cyclin-dependent kinases
(CDK; ref. 1). CDKs are activated through the formation of heterodimers with cyclins, whose concentration alters periodically
Received 7/20/09; revised 9/14/09; accepted 9/16/09; published OnlineFirst
11/24/09.
Grant support: European Social Fund and National Resources-(EPEAEK-II),
PYTHAGORAS II (grant number 7953), the European Commission funded
FP7-projects GENICA and INFLA-CARE and the SARG-NKUA grant
numbers: 70/3/1703, 70/4/9913, 70/4/4281.
Request for reprints Vassilis G. Gorgoulis, Antaiou 53 Str. Lamprini, Ano Patissia,
GR-11146 Athens, Greece. Phone: 30-210-7462352; Fax: 30-210-6535894. E-mail:
[email protected]
Copyright © 2009 American Association for Cancer Research.
doi:10.1158/1541-7786.MCR-09-0317
1902
during the cell cycle. Sequentially coordinated stimulation of different CDK-cyclin complexes ensures proper cell cycle progression (1).
On the other hand, inhibitory effects over the activity of
CDK-cyclin complexes may lead to cell cycle arrest (temporary
or permanent), differentiation, senescence, quiescence, or apoptosis (1). Important negative regulators of CDKs are the CDK
inhibitors (CKI).
There are two families of CKIs, the INK4 and the CIP/KIP
family. The INK4 family includes p16INK4a (2), p15INK4b (3),
p18INK4c (4), and p19INK4d (5, 6). The INK4 members are structurally related, having four ankyrin repeats. They cause G1 arrest
through competition with cyclin D, thus preventing formation of
active complexes of CDK4/6-cyclin D. The CIP/KIP family includes p21CIP1/WAF1/CDKN1A (7, 8), p27KIP2/CDKN1B (9, 10),
and p57 KIP2/CDKN1C (11, 12). The CIP/KIP family has a
broader specificity for CDKs than the INK4 members. At low
levels they bind to the CDK-cyclin heterodimer and promote
their assembly, whereas at high levels they abrogate CDK activity. In this review we focus on the younger and least studied
member of the CIP/KIP family, p57KIP2, presenting up-to-date
evidence about the regulation of p57KIP2, its physiologic functions, and its impact in human pathology, focusing on carcinogenesis, in comparison with p21CIP1/WAF1 and p27KIP1.
Structure of the CDKN1C Gene and mRNA
The human CDKN1C gene resides in the telomeric end of
chromosome 11, at the 11p15.5 locus (Fig. 1A; ref. 12). Mouse
and rat p57KIP2 reside in the distal region of chromosomes 7 and
1, respectively (13, 14). The coding region of CDKN1C consists
of four exons separated by three introns (Fig. 1A; ref. 15).
p57KIP2 is rich in CpG islands both upstream and downstream
of the putative transcriptional start site (16). Analysis of the
CDKN1C promoter revealed the following consensus binding
sites: (i) several Sp-1 (Stimulatory protein-1), (ii) ETS (erythroblastosis virus E26 oncogene), (iii) a TATA box [TBP (TATA box
binding protein)], (iv) EGR1 (early growth response 1), (v)
OCT1 (octamer-binding transcription factor 1), (vi) NF1 (neurofibromin 1), (vii) two CAT elements, (viii) a GRE (glucocorticoid response element), (ix) a binding site for the p63 isoform
ΔNp63α, and (x) binding sites for the Hes1 (hairy and enhancer
of split 1) and Herp2 (hes-related repressor protein 2) notch effectors (Fig. 1A; refs. 15, 17-21).
Alternative splicing of p57KIP2 intron 1 at different 3′ splice
acceptor sites produces three transcripts (Fig. 1A). The major
transcript corresponds to the one with the whole intron 1 spliced
out (15). The splicing and expression pattern is conserved among
humans and rodents (14).
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A p57KIP2 Review
FIGURE 1. Structure of p57KIP2 gene and p57KIP2 protein; comparison with p27KIP1 and p21CIP1/WAF1 proteins. Ai. Ideogram of human chromosome 11. Aii.
Schematic of the 11p15.5 subchromosomal region. The human p57KIP2 gene is located in the centromeric region of 11p15.5. It is transcribed from the maternal
allele (large arrow), because of imprinting of the paternal allele. However, there is a leaky expression from the paternal allele (small arrow). Aiii. Structure of the
human p57KIP2 gene. Transcribed regions (exons, Ex) are denoted in green boxes, with the coding regions hatched. Introns are depicted with red boxes. The human
promoter encompasses several consensus binding sites for a series of transcription factors. Owing to a space limitation in the figure, see text for a full description of
the transcription factors binding to the p57KIP2 gene promoter. Aiv. Splicing pattern of p57KIP2 mRNA. Three transcripts are produced because of alternative splicing
of intron 1 at 3′ different acceptor sites. A3 is the major transcript produced from whole intron-1 splicing out. B. Mouse and human p57KIP2 proteins are conserved in
the amino- and carboxy-terminal domains. The internal regions in mouse have been substituted in human with the PAPA domain, which is unique among the CIP/KIP
members. The amino-terminal region is highly homologous between all human CIP/KIP members encompassing the CDK inhibitory domain. The CDK inhibitory
domain possesses the cyclin-binding domain, the CDK-binding domain, and the 310 helix (orange boxes). The carboxy-terminal domain of human p57KIP2 has
similarities with both p21CIP1/WAF1 (PCNA-binding domain) and p27KIP1 (QT box). The PCNA-binding domain is not depicted in the mouse p57KIP2 carboxy-terminal
domain, because, according to Watanabe et al. (28), mouse p57KIP2 exhibits a much weaker PCNA binding activity than human p57KIP2.
p57KIP2 Protein
Structure of p57KIP2 Protein
Human and mouse p57KIP2 encode a 316- and a 335-amino
acid protein, respectively, both migrating as 57 kD by SDSPAGE electrophoresis (12). Mouse p57KIP2 protein consists
of four distinct domains: (i) domain I (located in the amino-
terminal region), a CDK inhibitory domain, sharing significant
homology with the respective CDK inhibitory domain of
p21CIP1/WAF1 and p27KIP1; (ii) domain II, a proline rich region;
(iii) domain III, comprising an exceptional acidic repeat, in
which every fourth amino acid is glutamic or aspartic acid;
and (iv) domain IV (located in the carboxy-terminal region),
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containing a conserved motif, named QT box (Fig. 1B). The
QT box domain is significantly homologous with the carboxyterminal domain of p27KIP1. The human and mouse p57KIP2
amino- and carboxy-terminal domains are conserved, whereas
the internal domains in the mouse p57KIP2 have been substituted in human p57KIP2 with a distinct domain rich in prolinealanine repeats, named the PAPA region (Fig. 1B; ref. 12). A
putative nuclear localization signal (NLS) has been recognized
in the QT box domain of the mouse p57KIP2, similar to the NLS
in the carboxy-terminal of mouse p21CIP1/WAF1 and mouse
p27KIP1 (11).
Spectroscopic and hydrodynamic analysis indicate that
human p57KIP2 lacks a stable helical and β-sheet structure,
although the formation of a secondary structure cannot be precluded (22). p57 KIP2 as well as p21 CIP and p27 KIP1 are
considered to be highly unfolded molecules (23, 24). Proteins
that are fully or partially unfolded show a binding plasticity at
the expense of thermodynamic stability, are degraded faster,
and have an increased rate of evolution compared with folded
proteins (25-27). CIP/KIP family members have a broad
specificity for CDKs and are short-lived proteins that may
be attributed to their internal regional structure.
The p57 KIP2 Protein Interactions: Comparison with
p21CIP1/WAF1 and p27KIP1
p57KIP2 binds with CDKs in a cyclin-dependent manner
(12). Association of p57KIP2, with cyclins only, is very weak.
p57KIP2 inhibits in vitro the activity of the following CDKcyclin complexes: CDK2-cyclin E, CDK2-cyclin A, CDK3cyclin E, CDK4-cyclin D1, CDK4-cyclin D2, and to a lesser
extent CDK1(CDC2)-cyclin B and CDK6-cyclin D2 (11, 12,
28). At low concentrations p57KIP2 can form active complexes
with CDK2-cyclin A, enhancing their assembly, whereas at
higher levels p57KIP2 inhibits the kinase activity of CDK2
(29). Similarly, CDK4-cyclin D1-heterodimer formation and
activity is regulated in a p57 KIP2 dose-dependent manner
(28). This property is in accordance with the ability of both
p21CIP1/WAF1 and p27KIP1, at low concentrations, to promote
FIGURE 2. Imprinting control regions of 11p15.5. The human chromosomal region 11p15.5 encompasses the H19-ICR (ICR-1) and the KCNQ1/KvDMRICR (ICR-2). H19-ICR is responsible for the imprinting status of several genes located in the telomeric end of 11p15.5 including H19 and IGF2. It is imprinted
in the paternal allele (orange-dotted box), leading to the activation of the paternal IGF2 and to the suppression of the maternal H19. KCNQ1/KvDMR-ICR is
located within intron 10 of the KCNQ1 gene in the promoter region of a noncoding antisense transcript named KCNQ1OT1/KvLQT1AS/LIT1. KCNQ1/KvDMRICR affects the imprinting status of the centromeric region of 11p15.5. The imprinting of the maternal ICR-2 (orange-dotted box) is associated with the
suppression of the maternal LIT1 and the expression of the maternal genes p57KIP2 and KCNQ1. The arrows and the green boxes depict the active alleles,
whereas the red boxes show the silent alleles.
Mol Cancer Res 2009;7(12). December 2009
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A p57KIP2 Review
FIGURE 3. Methylation analysis of p57KIP2 promoter in normal and tumor human lung specimens. A. Methylation-specific PCR analysis shows promoter
methylation in both normal (N) and tumor (T) lung tissue in a representative case. M+ and M- denote the methylation-specific PCR analysis with primers
designed to bind specifically to methylated and nonmethylated CpG islands, correspondingly. B. Pyrosequencing analysis of the same representative case
(depicted in A), showing decreased promoter methylation [assayed as methylation index (MtI)] in the tumor (T) versus the corresponding normal (N) tissue.
Note the different scale in the y-axis of the pyrosequencing diagram.
the assembly of CDK4-cyclin D complex, whereas at higher
levels to abrogate the kinase activity of the CDK-cyclin
heterodimers (30-32).
The amino-terminal region of CIP/KIP members is necessary and sufficient for the inhibition of CDK-cyclin activity.
It consists of three sites that are involved in the suppression
of CDK-cyclin activity, a cyclin binding region, a CDK binding
site, and a 310 helix (Fig. 1B). The 310 helix contains a phenylalanine-tyrosine pair of amino acids that is bound to the aminoterminal of CDK2, inside the catalytic cleft, mimicking the
purine base of adenosine triphosphate (24). The 310 helix is
indispensable for the in vivo inhibition of CDK2-cyclin A
and CDK2-cyclin E by p57KIP2, but not for p21CIP1/WAF1 and
p27KIP1 (29).
It has been proposed that the central region of p57KIP2 may
serve as an important domain for protein interactions implicated
in functions other than the CDK-inhibitory role (15). Indeed, the
central region of mouse p57KIP2 interacts with the N-terminal of
LIMK-1, a downstream effector of Rho (analyzed in the Cytoskeletal Organization section; ref. 33). The carboxy-terminus
of p57KIP2 binds in vitro with proliferating cell nuclear antigen
(PCNA) with a much lower affinity than p21CIP1/WAF1 (34). In
addition, p57KIP2 interacts with and inhibits the kinase activity
of c-Jun NH2-terminal kinase/stress-activated protein kinase
(JNK/SAPK) through its QT domain (35). Interestingly,
p27KIP1 does not inhibit JNK/SAPK activity, although it contains
a QT domain (35). p21CIP1/WAF1 also has the ability to bind and
suppress the activity of JNK/SAPK via the amino-terminal domain (36). p57KIP2, but not p21CIP1/WAF1 or p27KIP1, interacts
both in vivo and in vitro through its amino-terminal domain
with the transcription factor B-Myb (37). B-Myb competes with
Cyclin A2 for the association with p57KIP2. Overexpression of
B-Myb partially overwhelms the G1 cell cycle arrest induced
by p57KIP2 in Saos-2 cells.
Expression and Tissue Distribution Pattern of
p57KIP2
A highly cell-specific, temporal and spatial p57KIP2 expression profile has been found during the fetal, the postnatal, up to
puberty, and the adult life cycle. Most of the data have been
obtained from rodents (14, 38-44) and only sporadically in humans (11, 12, 44, 45). Specifically, the highest levels and most
widespread tissue localization were observed during organogenesis. p57KIP2 is present in all major organs during embryonic development, and its levels of expression peaks at key stages
of differentiation for each specific organ (14, 39, 41). Afterward, its expression declines to low or undetectable levels in
several tissues (14, 39, 41), and only organs that mature after
birth, such as testis (44), exhibit strong p57KIP2 staining in
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certain tissue compartments. Comparatively to prenatal tissues,
fewer adult tissues continue to abundantly express p57KIP2 (11,
12). Nevertheless, an age-dependent p57KIP2 decline in some of
these tissues has also been reported (42).
Human adult tissues expressing significant p57KIP2 mRNA
levels are mainly skeletal muscle, brain, heart, lung, kidney,
pancreas, testis, and placenta (11, 12); this is in contrast
with the wider tissue distribution of higher levels of human
p21 CIP1/WAF1 and p27 KI P1 mRNA (11, 12). In rodents,
p57KIP2 expression correlates, on average, with the human
distribution pattern (12, 14, 39, 41), but a few species-specific
exceptions do exist (14, 39, 41, 44).
Regulation of p57KIP2
Transcriptional Regulation of p57KIP2
Epigenetic control has emerged as an important mechanism
for the transcriptional regulation of p57KIP2. The genetic locus
of human p57KIP2, 11p15.5, harbors several imprinted genes
(Fig. 2). Genomic imprinting refers to the differential epigenetic modulation of a gene leading to a parent-of-origin specific
expression. This term means that the maternal and paternal allele of an imprinted gene display different properties, despite
the fact that they have identical sequences. Epigenetic mechanisms include modulations of DNA methylation within CpG islands, chromatin remodeling (covalent modifications of
histones), and silencing from various types of noncoding
RNA transcripts (46). Methylation of DNA within CpG doublets, as well as methylation and deacetylation, in the aminoterminal tails of histones H3 and H4 are related with an inactive
gene state, whereas the opposite is associated with gene activation. The cluster of imprinted genes in specific chromosomal
regions, suggests that they share a common regulatory mechanism. The imprinting of such clusters is regulated by specific
sequences acting in cis, known as imprinted control regions
(ICR). ICRs encompass the following features: (i) a differentially methylated region (DMR) and chromatin conformation
status between the maternal and the paternal genome and (ii)
the establishment of the imprinting marks during gametogenesis, because this is the only developmental period in which the
maternal and paternal genome are separated (47, 48).
The linkage of genes within the 11p15.5 region and the
mouse homolog on distal chromosome 7 is conserved, showing
the significance of the integrity of this region for the proper imprinting of the genes located therein (49-51). The regulation of
imprinted genes in 11p15.5 is controlled by two ICRs, H19-ICR
(ICR1) and KCNQ1/KvDMR-ICR (ICR2; Fig. 2). H19-ICR is
located in the telomeric end of 11p15.5 and influences the imprinting of H19 and IGF2 by functioning as a chromatin insulator, restricting the access to shared enhancers (52). H19 is
maternally expressed, whereas IGF2 is paternally transcribed.
The KCNQ1-ICR coordinates the imprinting status of the more
centromeric domain of 11p15.5 encompassing p57KIP2 and
KCNQ1/KvLQT1 (53-56). p57KIP2 is maternally expressed,
however there is a leaky expression from the paternal allele in
most human tissues (57). The imprinted status of p57KIP2 is conserved between mice and human (13). p57KIP2 is hypomethylated in normal human kidneys (58), whereas we showed
promoter methylation in normal human bronchial tissue
(Fig. 3; ref. 59), suggesting the involvement of tissue-specific
FIGURE 4. Multiple roles of
p57KIP2 in cell biology. A. Positive p57KIP2 immunostaining in
mitosis (arrowhead) and in the
nucleus (arrows) in the cancerous region of a representative
case. B. Positive cytoplasmic
p57 KIP2 immunostaining of a
cancer cell (arrowhead) from a
representative case. C. Putative role of p57KIP2 in apoptosis
and senescence.
Mol Cancer Res 2009;7(12). December 2009
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A p57KIP2 Review
FIGURE 5. p57KIP2 has a
vital role in development.
p57KIP2−/− mice have increased postnatal lethality
and exhibit severe developmental defects in comparison
with p21CIP1/WAF1−/− and
p27KIP1−/− mice.
mechanisms in the imprinting control of p57KIP2. Treatment
with 5′-azacytidine, a demethylating agent, and/or trichostatin,
a histone deacetylase inhibitor, activates p57KIP2 expression in
mouse embryo fibroblasts, showing that both CpG methylation
and histone deacetylase activities are involved in p57KIP2 imprinting (60). KCNQ1 is maternally expressed and harbors in
intron 10 an antisense orientated nontranslated transcript named
KCNQ1OT1/KvLQT1AS/LIT1 (long QT intronic transcript 1),
which is paternally expressed (53-55). The KCNQ1-ICR coincides with the promoter of LIT1 in both human and mice
(Fig. 2; refs. 53, 55, 61). The KCNQ1-ICR encompasses the
typical characteristics of an ICR; it carries DNA methylation
and acquires a repressive chromatin structure on the maternal
allele, and the imprinting marking is established from the female
germline (53-55, 62-64). The imprinting status of KCNQ1-ICR
is associated with the expression pattern of the centromeric
genes of 11p15.5, including p57 KIP2 . Specific regulatory
elements within or in the flanking region of the KCNQ1 gene
possibly act at a distance and regulate the expression of
p57KIP2 according to the imprinting status of KCNQ1-ICR (6570). The disruption of p57KIP2 imprinting in p57KIP2 transgenic
lines supports the significance of cis-elements that are important
for p57KIP2 expression lying at distance from the gene (71, 72). A
functional role for LIT1 is also supported, participating in the
establishment of the imprinting status of p57KIP2 (73-75), similar
to the function of Xist on X chromosome inactivation (76) and of
the noncoding Air on the IGF2R locus (77). In marsupials LIT1 is
expressed in the absence of p57KIP2 imprinting, suggesting a
step-by-step evolutionary accumulation of these epigenetic
mechanisms within the p57KIP2 region (78, 79).
Recently, a series of micro-RNAs (miR) have been reported
to down-regulate the expression of p57KIP2, either specifically
or along with other CIP/KIP members. Particularly, miR-221
and miR-222, which belong to the same cluster, are known
from bioinformatic analyses to target both p57KIP2 and p57KIP2
(80-82). This effect has been validated in various human cell
lines and in vivo in human hepatocellular and gastric carcinomas
(80-83). In gastric cancer, p57KIP2 expression is also regulated by
miR-25 (81), whereas in human embryonic stem cells it is specifically targeted by miR-92b (84). Functional analyses have
shown that miR-dependent CIP/KIP silencing results in a shift
in the number of cells from G1 to S-phase (80-82, 84). In murine
embryonic stem cells and neural stem cells derived from embryonic stem cells, miR-106b and miR-17-92 suppress p57KIP2 and
p21CIP1/WAF1 and promote renewal of these stem cells (85).
Numerous other pathways control the expression of p57KIP2,
possibly through activation of epigenetic mechanisms. In this
context, the proteins SMARCB1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b,
member 1) and CITP2 (chicken ovalbumin upstream promoter
transcription factor interacting protein 2) up-regulate and correspondingly suppress p57KIP2 expression through chromatin
remodeling (86, 87). Histone methyltransferase EZH2 can suppress p57KIP2 through histone H3 lysine 27 trimethylation
(H3K27me3; ref. 88). Histone deacetylase inhibitors enhance
the recruitment of Sp1 transcription factor in the promoter of
p57KIP2, inducing its expression (89). The p53-related family
member p73β induces the expression of p57KIP2 by activating
the transcription of the nonsilent maternal allele (90). Interestingly, it was found that p73β isoform up-regulates the expression of both p57KIP2 and KCNQ1 without affecting the status of
LIT1. p53 failed to induce p57KIP2, although it transcriptionally
activates p21CIP1/WAF1 (12, 90, 91). The fact that p57KIP2−/−
mice share a similar phenotype with p63−/− mice prompted Beretta and colleagues (17) to examine the possibility of a link
between these two proteins. Indeed, the p63 isoform ΔNp63α
binds to p57KIP2 promoter and induces its activation (17). The
CDK inhibitor BMS-387032 up-regulates p57KIP2 through the
transcriptional factor E2F1 in a direct manner (92). Induction
of p57KIP2 after drug treatment, in turn, restrains E2F1 activity,
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serving as a negative feedback loop. Transforming growth factor
β1 (TGFβ1) induces p57KIP2 in human hematopoietic cells,
leading to cell cycle arrest (93). Silencing of p57KIP2 abrogates
the TGFβ1- induced decrease in proliferation of primary
human limbal epithelial cells (94). TGFβ induces p27KIP1 and
p21CIP1/WAF1 as well (95, 96). Insulin-like growth factor 2
(IGF2) down-regulates p57KIP2 in vivo in a dose-dependent manner (97). The Notch effectors Hes1 and Herp2 bind to and suppress the expression of p57KIP2 (18, 19). Hes1 also directly
suppresses the expression of p27KIP1 (98). p57KIP2, but not
p21CIP1/WAF1 or p27KIP1, is induced by the transcription factor
E47 that participates in human development, consistent with
the unique role of this member of CIP/KIP family in embryogenesis (analyzed below; ref. 99). Interestingly, inhibitor of differentiation 2 (Id2), a natural inhibitor of E47, suppresses p57KIP2. The
chimeric protein PAX3-FOXO1, often present in rhabdomyosarcoma, reduces p57KIP2 expression via the repression of the GC
box-binding factor EGR1 (100). PLAG1/ZAC1 is an imprinted
gene selectively expressed from the paternal allele from chromosomal region 6q24 (101). It has been shown that ZAC1 affects the
expression of p57KIP2 (101, 102). Human and mouse p57KIP2 promoter contains a functional glucocorticoid response element (20).
The induction of p57KIP2 upon glucocorticoid treatment may
be responsible for the antiproliferative effects of glucocorticoids
(103). The antigrowth effect of atrial natriuretic peptide may be
partially mediated by the fact that it induces p57KIP2 and p27KIP1
as well (104). The vitamin D3 analog EB1089 inhibits the
proliferation of the human laryngeal squamous cell carcinoma
(Hep-2) through the induction of p57KIP2 (105). Kido and colleagues (106) have shown that exon-2 of p57KIP2 encompasses a
functional Bel1 response element, activated by the Bel1 transactivator of the human foamy virus.
Post-translational Regulation of p57KIP2
Ubiquitylation and subsequent proteasomal degradation play
a significant role in the regulation of p57KIP2 protein levels.
The SKP1-CUL1-F-box (SCF) complex is part of the ubiquitin-proteasome pathway and mediates ubiquitylation of target
proteins from late G1 to early M phase. It consists of three constant subunits, named SKP1, CUL1, and RBX1, and a variable
FIGURE 6. Multiple epigenetic and genetic defects in the 11p15.5 chromosomal region are responsible for the phenotypic heterogeneity of Beckwith-Wiedemann
Syndrome. Loss of imprinting of ICR-2 leading to the silencing of the p57KIP2 gene accounts for the majority of cases with BWS. Uniparental disomy 11 (UPD11)
represents a genetic abnormality because of abnormal chromosomal recombination leading to double dose of IGF2 and suppression of p57KIP2. Loss of imprinting of
ICR-1 causing double dose of IGF2 is a less frequent event in comparison with loss of imprinting of ICR-2 in BWS. Mutations in p57KIP2, located mainly in the CDKinhibitory or in the QT box/PCNA-binding domain, are implicated in the pathogenesis of BWS. In this figure we present the four most frequent mechanisms related to
the pathogenesis of BWS. The sum of all above percentages is less than 100%, as other mechanisms (most of them are still unknown) are also responsible for the
pathogenesis of BWS. The arrows and the green boxes denote active genes, whereas the red boxes show inactive genes.
Mol Cancer Res 2009;7(12). December 2009
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A p57KIP2 Review
Table 1. Summary of the Results from the In vivo Studies of p57KIP2 Aberrations in Several Types of Cancer
Type of Cancer
Alterations in p57KIP2
References
KIP2
No mutations, frequent LOH in 11p15.5 (with a maternal bias) associated with decreased p57
mRNA; reactivation of the paternal p57KIP2 (LOI) in tumors with LOH; p57KIP2 expression varies
Soft tissue sarcomas
No mutations
Hepatoblastoma
No mutations; LOH with a maternal bias; increased mRNA expression of p57KIP2
ALL, LMB
ALL: Downregulation of p57KIP2 (increased methylation of p57KIP2 promoter is partially associated
with its decreased expression); AML: increased methylation of p57KIP2 promoter; LMB: no mutations,
increased methylation of p57KIP2 promoter
AC and GBM
AC: no mutations; GBM: decreased expression of p57KIP2
Oral squamous cell carcinoma
No mutations; LOH with no parental bias; increased mRNA expression in cases with LOI; decreased
positive immunostaining of p57KIP2 protein
Laryngeal squamous cell carcinoma Decreased positive immunostaining of p57KIP2 protein
Lung carcinomas
No mutations; frequent LOH with a maternal allele bias; increased methylation of p57KIP2 promoter
(non-small cell lung carcinomas) (and in a few cases upregulation of LIT1) related with decreased expression of p57KIP2;
faint p57KIP2 positive immunostaining in tumor versus normal tissues; diminished p57KIP2
protein status associated with increased SKP2
Esophageal squamous carcinoma
p57KIP2-positive immunostaining at relatively high frequency in tumors
Gastric carcinoma
No mutations; increased levels of miR-25, miR-221, and miR-222 (target p57KIP2)
PC and IPMN
PC: p57KIP2-positive immunostaining decreases in cases with high biologic aggressiveness; IPMN:
Decreased transcriptional and translational levels of p57KIP2 associated with promoter hypermethylation.
A subset of specimens exhibited LIT1 hypomethylation because of deletion of the methylated LIT1 allele.
HC and EIC
HC: no mutations; downregulation of p57KIP2 related to loss of LIT1-ICR methylation; reduced
positive immunostaining of p57KIP2 in cases with high biological aggressiveness; downregulation
of p57KIP2 protein associated with upregulation of miR-221; EIC: Decreased expression of
p57KIP2 in cases with biological aggressive phenotype;
Colorectal carcinoma
Decreased positive immunostaining of p57KIP2 in colorectal carcinomas
Bladder carcinoma
No mutations; diminished expression of p57KIP2 mRNA correlated in some cases with LOH;
decreased expression of p57KIP2 positive immunostaining
Breast carcinoma
No mutations; Increased methylation of p57KIP2 promoter; decreased transcriptional levels and
diminished positive immunostaining of p57KIP2
Ovarian carcinoma
Intense positive immunostaining of p57KIP2; decreased positive immunostaining in cases with
high biological aggressive phenotype
Malignant adrenocortical tumors
Reduced mRNA expression of p57KIP2
Thyroid carcinomas
Decreased p57KIP2 positive immunostaining in cases with biological aggressive phenotype
Wilms' tumor
58, 212-217
213
218
ALL: 219-222;
AML: 16; LMB: 223
126, 211
224, 225
226
59, 227, 228
246
81, 229
PC: 231, 230;
IPMN: 247
HC: 15, 80, 232-236;
EIC: 237
248
15, 238, 239, 249
15, 88, 227, 240
241, 242
243, 244
245
Abbreviations: AC, astrocytoma; ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; EIC, extrahepatic bile duct carcinoma and intrahepatic cholangiocellular carcinoma; GBM, glioblastoma; HC, hepatocellular carcinoma; IPMN, intraductal papillary mucinous neoplasm; LMB, lymphoid malignancies of B-cell origin;
LOH, loss of heterozygosity; LOI, loss of imprinting; PC, pancreatic carcinoma.
component, an F-box protein that determines the target protein
(107). The S-phase kinase-associated protein 2 (SKP2) belongs
to F-box proteins. SKP2 interacts with p57KIP2 and promotes its
degradation in a phosphorylation-dependent manner (108).
SKP2 also mediates the degradation of p21 CIP1/WAF1 and
p27KIP1 (107). TGFβ1 stimulation induces p57KIP2 degradation
via Smad-mediated transcription in serum-starved mouse osteoblasts (109, 110). TGFβ1 up-regulates the expression of a novel
F-box protein, called FBL12, responsible for the mediation of
p57KIP2 degradation in a SKP2-independent manner in osteoblast cells and 293T cells originating from human kidney
(111). The fact that TGFβ1 induces p57KIP2 in human hematopoietic and limbal epithelial cells may reflect tissue-specific
regulation of p57KIP2 or alternatively reveal different regulatory
mechanisms between mice and humans (93, 94). A recent study
showed that p57KIP2 participates in the TGFβ-compensatory
tubular hypertrophy in unilaterally nephrectomized male Sprague-Dawley rats, suggesting a positive correlation between
TGFβ and p57KIP2 in this type of tissue (112).
Functions of p57KIP2
Cell Cycle Control
The role of the CDK inhibitors p21CIP1/WAF1 and p27KIP1
in cell cycle arrest is well established (96, 113). In accordance with the other CIP/KIP family members, induction
of p57KIP2 causes cell cycle arrest in G1 phase (11, 12).
Transfection of SAOS-2 (sarcoma osteogenic, p53−/−, and
Rb−/−) cells with the full-length p57KIP2 and a truncated
p57KIP2, in which the carboxy-terminal is omitted, led to
G1 arrest (12). This finding is in agreement with the fact that
the amino-terminal of p57KIP2 is indispensable for cell cycle
arrest, through the inhibition of activity of the Cyclin-CDK
complexes. In accordance with the above, induction of
p57KIP2 in R-1B/L17 (subclone of the Mv1Lu mink lung epithelial cell line) caused cell cycle arrest in G1 phase (12).
Endoreduplications are successive oscillations of G and S
phases in the absence of mitosis and cytokinesis (114).
The protein levels of p57KIP2 alter periodically during subsequent endoreduplications of trophoblast giant cells, diminishing before S-entry and reappearing after the completion of S
phase (115). Introduction of a stable form of p57KIP2 into
trophoblast giant cells blocks G1- to S-phase transition
(115). A role of p57KIP2 in endoreduplication is reinforced
by the fact that p57KIP2 triggers endoreduplication in mouse
trophoblast stem cells by suppression of CDK1 activity
(116). In the same study, p21CIP1/WAF1 and p27KIP1 could
not compensate p57KIP2 for its role in endoreduplication in
trophoblast stem cells. Moreover, p57KIP2 participates in
the M-to-G1 transition through activation by p73 (100).
Abrogation of p73 or its downstream effector p57 KIP2
perturbs mitotic progression and transition to G1 phase
(Fig. 4A; ref. 117).
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Cytoskeletal Organization
p57KIP2 has a nuclear distribution, consistent with its antiproliferative capacity (11). However, it has been shown that
p57KIP2 may accumulate in the cytoplasm participating in the
regulation of the cytoskeletal dynamics (33). Mouse p57KIP2
binds, through its central domain, to LIM-kinase-1 and translocates it from the cytoplasm to the nucleus, without abrogating
its kinase activity. LIM-kinase-1 is a serine-threonine kinase
that phosphorylates and inactivates an actin depolymerization
factor cofilin, leading to the stabilization of actin stress fibers
(118). Our laboratory provided evidence for the specificity of
human cytoplasmic p57KIP2 localization in normal and cancerous material from lung (Fig. 4B; ref. 59). p21CIP1/WAF1 and
p27KIP1 also have a distinct function in the cytoplasm, different
form the cyclin-CDK inhibitory role. They have the ability to
regulate the Rho signaling pathway, therefore interfering with
cytoskeletal organization (119). Altogether it seems that the
CIP/KIP members participate in the interconnection between
cell cycle control and cytoskeletal organization.
Putative Role of p57KIP2 in Apoptosis and Senescence
p57 KIP2 enhances staurosporine-induced apoptosis in
human cervical adenocarcinoma cell line (HeLa) cells in a
CDK-inhibitory independent manner (120). p57KIP2 translocates to mitochondria and activates the intrinsic apoptotic
pathway (121). Targeted silencing of p57KIP2 suppresses the
p73β-mediated apoptosis in the lung cancer cell line H1299
and in the colorectal carcinoma cell line HCT116 caused by
cisplatin treatment (122). Upregulation of p73β in postmitotic
hNT neurons induces p57KIP2 and BAX leading to apoptosis
(123). In contrast, p57KIP2 suppresses JNK/SAPK mediated
apoptosis in the human embryonic kidney cell line HEK293
after exposure to UV light, demonstrating an anti-apoptotic role
of p57KIP2 (35). Similarly, induction of p57KIP2 by BMS387032 has a strong antiapoptotic effect on the MDAMB-231 cell line (92). A dual role in apoptosis has been
documented for p27 KIP1 and p21CIP1/WAF1, although most
reports confer, especially for p21CIP1/WAF1, an anti-apoptotic
role (95, 119, 124). We have not found an association of
p57KIP2 or p27KIP1 with apoptosis neither in vivo in non-small
cell lung cancer specimens nor in vitro in the A549 lung cancer
cell line (59, 125). The role of CIP/KIP members in apoptosis
may be tissue specific, dependent on the intracellular localization and the pathway they target (Fig. 4C). CIP/KIP members
also play a role in cellular senescence. The induction of p57KIP2
in human astrocytoma cell lines restrains their proliferation
and induces a senescent phenotype (126). Similarly, upregulation of p57KIP2 in the PPC-1 prostate cancer cell line induces a
senescence-like phenotype (127). However, more studies are
required to clarify the relation of p57KIP2 with cellular senescence (Fig. 4C), in contrast to the well-established role of
p21CIP1/WAF1 (96).
Lessons from Mice
Mice lacking p57KIP2 (p57KIP2−/−) display increased postnatal mortality accompanied by severe developmental abnormalities (Fig. 5; refs. 128-130). Mice with targeted disruption of
p57KIP2 exhibit limb shortening owing to abnormal endochondral ossification, cleft palate, omphalocoele, gastrointestinal
tract defects, adrenal cortex enlargement, renal medullary dysplasia, abnormalities in lens fiber cells, and increased body
weight (128-131). Surviving mice exhibited severe growth retardation, immaturity of testes and uterus, and vaginal atresia
(130). Mice with targeted deletion of the maternal p57KIP2 allele
showed similar phenotypic abnormalities with p57KIP2−/− mice
(128, 129). The observed developmental defects occur possibly
because of delayed differentiation and increased apoptosis. Excess p57KIP2 in mice leads to increased embryonic lethality and
to decreased body size, suggesting that embryonic growth is
sensitive to p57KIP2 dosage (131). Endochondral bone formation is compromised in null mice for either parathyroid hormone-related peptide (PTHrP) or p57 KIP2 , in an opposite
manner (128, 129, 132, 133). In PTHrP/p57KIP2-null mice,
the absence of p57KIP2 partially normalizes the PTHrP-null phenotype (133). Mutant mice lacking either both p57KIP2 alleles or
only the maternal one, with the paternal allele intact, display severe placental abnormalities including trophoblastic dysplasia
(134). Diminution of p57KIP2 expression in mouse placenta
did not alter the activity of both CDK2 and CDK4, providing
evidence for a biological role of p57KIP2 in placenta, different
from the inhibition of the CDK activity. p21CIP1/WAF1 knockout
mice (135, 136) and p27KIP1 null mice (137-139) do not exhibit
gross developmental abnormalities, revealing the importance of
p57KIP2 in embryonic development in relation with the other
CIP/KIP members (Fig. 5). Interestingly, mice lacking both
p21CIP1/WAF1 and p57KIP2 exhibit all the phenotypic alterations
caused by p57KIP2 null mice alone, but also express novel
abnormalities in lung, skeleton, and skeletal muscles, demonstrating the cooperation between these proteins in mouse development (38). The frequency of embryonic lethality increases
in p57 KIP2 and p27 KIP1 double null mice compared with
p27 KIP1−/+ p57 KIP2P+/M− (140). Moreover, p27 KIP1−/− and
p57KIP2−/− mice exhibit more severe developmental defects in
placenta and lenses than p27KIP1−/− mice alone, showing the
significance of p57KIP2 in development. Immunohistochemical
analysis of p57KIP2 and p27KIP1 in certain tissues from mice revealed a mutual pattern of expression, suggesting the importance of both KIPs for proper development (39). Susaki and
colleagues (141) created a knock-in mouse model in which
the p57KIP2 gene was replaced with p27KIP1 gene. In this model
the mice are viable and phenotypically healthy, revealing the
partial functional redundancy between the KIP members.
The Role of p57KIP2 in Cooperation with p21CIP1/WAF1 and
p27KIP1 in Development
The fact that p57KIP2 is expressed during mouse embryogenesis in several anatomical structures underlies its role in embryonic development (128, 129). Specifically, p57KIP2 is found in
derivatives of all three germ layers, the ectoderm, mesoderm,
and endoderm, and in all major organs of the developing fetus
(14, 39, 41). The earliest expression in rodents is between
E9.0 and E10.5 in the heart (14, 39, 41). As mentioned above
in the Expression and Tissue Distribution Pattern of p57KIP2
section, the highest p57KIP2 expression coincides with the
stage of differentiation for each specific organ (14, 39, 41). Importantly, the strongest p57KIP2 expression appears at the interface of developing tissues with different embryonic origin,
as in the direct contact between epithelial and mesenchymal
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tissues (41). Comparative analyses of all three CIP/KIP
family members during rodent prenatal development have
revealed a complex spatial and temporal pattern of expression
(38-40, 43, 140). Of note, cyclin D3, a p57KIP2 inhibition
target, also exhibits a specific temporal and spatial expression
pattern in differentiating mammalian tissues, as well as in
relation to the other cyclin D members (142). Yet, with a
few exceptions, no systematic correlation has been done
with the corresponding p57KIP2 temporal and spatial pattern
of expression.
p57KIP2 cooperates with negative (p27KIP1) and positive
(CDK2, CDK4, cyclin D, and cyclin E) cell cycle regulators
to promote lens fiber differentiation (140, 143, 144). Particularly, it has an opposite effect on the proliferating function of cyclin D3 (144). p57KIP2 and p27KIP1 participate in mouse retina
development through the induction of cell cycle exit in the retinal progenitor cells, but in mutually different subpopulations
(145). Downregulation of p57KIP2 and p27KIP1, through Notch
signaling, inhibits mouse lens epithelia differentiation (19,
146). p57KIP2 has two distinct roles in mouse retina, it controls
proliferation of progenitor cells and promotes the development
of amacrine interneurons (147). In addition, p57KIP2 promotes
cell cycle exit of precursor cells in zebrafish retina through its
activation by the Sonic hedgehog (Shh; ref. 148).
p57KIP2 participates in the development of the nervous system (149). It collaborates with p27KIP1 on the regulation of neuronal migration of mouse cortex (150) and rat neurogenesis
(151); it promotes oligodendrocyte differentiation (152, 153);
and is required for the maturation of dopamine neurons
(154). Downregulation of p57KIP2 mediates in vitro myelination
by Schwann cells (155).
p57KIP2 participates in myogenesis (38). It stabilizes MyoD, a
muscle-specific transcription factor involved in myogenic
differentiation, through the inhibition of the phosphorylationdependent degradation by cyclin E-CDK2 complex and by direct
association of the amino-terminal domain of p57KIP2 with the basic helix-loop-helix domain of MyoD (156-158). In turn, MyoD
up-regulates p57KIP2 in a p73-dependent manner (159). MyoD
induces p21CIP1/WAF1 in a direct manner (158). Notably, cyclin
D3 also participates in striated muscle cell differentiation
(142), but no link has been established with p57KIP2.
Interestingly, as podocytes progress to terminal differentiation they are characterized by an increase in both p57KIP2
and cyclin D3, along with a decrease in the levels of cyclin
D1 (160).
Differential immunohistochemical staining of p57KIP2 in human placenta cells suggests a role of p57KIP2 in human placenta
development (161). The coordinated expression of the CIP/KIP
members promotes keratinocyte differentiation (162, 163). During pancreatic development p57KIP2 controls both self-renewal
and cell cycle exit of pancreatic progenitors (18). p57KIP2 and
p27KIP1 cooperate in a temporal manner for pituitary development; p57KIP2 promotes cell cycle exit of progenitors, whereas
p27KIP1 prevents cell cycle reentry (164). p57KIP2 is also implicated in hepatocyte maturation (40), T-lymphocyte cell development (165), spermatogenesis and Leydig cell development
(45), hematopoiesis and hematopoietic stem cell cycle arrest
(93, 166), chondrocyte differentiation (133, 167), and in adrenal cortex development (168).
Overall, CIP/KIP members possibly share partial overlapping roles in embryogenesis, although p57KIP2 seems to have
the upper hand over p21CIP1/WAF1 and p27KIP1 in development.
The strong impact of p57KIP2 on embryo survival and development, along with its more complex internal structure relative to
its counterparts, which seems to keep differentiated organs under control postnatally and in adulthood, implies that p57KIP2
may have preceded the appearance of the other CIP/KIP
members evolutionarily.
p57KIP2 in Pathology
We analyze here the impact of p57KIP2 on human pathology,
apart from its role in carcinogenesis, which is examined separately below in the Role of p57KIP2 in Carcinogenesis section.
Several studies have shown the role of p57KIP2 in the pathogenesis of Beckwith-Wiedemann Syndrome (BWS; ref. 169).
BWS is a clinically heterogeneous disease, with most patients
exhibiting macrosomia, macroglossia, omphalocoele, and a
predisposition to pediatric tumors, including Wilms' tumor, hepatoblastoma, adrenocortical carcinoma, and rhabdomyosarcoma (170). The phenotypic heterogeneity of BWS reflects the
different epigenetic and genetic defects affecting the 11p15.5
domain (Fig. 6; refs. 171-174). The most frequent alteration
is loss of imprinting of the maternal LIT1 locus (ICR-2), leading to biallelic expression of LIT1, which is associated with reduced levels of p57KIP2 (53-55, 62, 173, 175, 176). Epigenetic
alterations in H19-ICR, related with upregulation of IGF2, is a
less frequent event (177). Patients with BWS exhibit mutations
of p57KIP2, more frequently seen in familial BWS (30–50%),
than in sporadic BWS (5–10%; ref. 177). p57KIP2 mutations
are mainly detected in the CDK-inhibitory domain and in the
QT box domain (172, 173, 178-182). Mutations in the CDKinhibitory domain abrogate the CDK2-inhibitory activity,
whereas mutations in the QT box domain retain the capability
of CDK2 suppression, but exclude the protein from the nucleus,
therefore in both cases the cell cycle inhibitory activity is compromised (181, 182). Mosaicism of paternal isodisomy of
11p15.5 [paternal uniparental disomy 11 (pUPD11)], accounts
for almost 20% of BWS cases (177). Uniparental disomy results from chromosomal rearrangements owing to abnormal
recombinations occurring in meiosis, mitosis, or successive
meiosis and mitosis (183). Tissues employing pUPD11, have
two paternal but no maternal copies of 11p15.5, exhibiting double dose of the growth-promoting paternally expressed IGF2
and diminished expression of the growth-inhibiting maternally
expressed gene p57KIP2 (46, 184). The existence of a predominant pUPD11 distribution in the abdominal organs of two fetuses with BWS exhibiting omphalocoele (185) is reminiscent
of the p57KIP2−/− phenotype in mice (129). Double mutant mice
with loss of function of p57KIP2 and with gain of function of
IGF2, mimicking pUPD11, display several similarities with
BWS phenotype (186).
Mutant mice, defective only for the maternal p57KIP2 allele
(p57KIP2-M/+P), display the whole spectrum of the clinical manifestations of pre-eclampsia including proteinuria and elevated
blood pressure (134, 187). The observed trophoblastic hyperplasia may be the leading cause (188). Further studies, failed
to recapitulate pre-eclampsia manifestations in the particular
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mouse model, although they invariably exhibited placenta abnormalities, suggesting the significance of environmental factors in the development of this disease (188, 189). Recently,
Romanelli and colleagues (190) reported the existence of three
women with haemolysis, elevated liver enzymes, and low platelets (HELLP)-preeclampsia who gave birth to children with
BWS possessing mutations in p57KIP2. Therefore, a possible
role of the imprinted gene p57KIP2 in the pathogenesis of preeclampsia is suspected, although further studies are needed to
clarify this issue. p57KIP2 is absent in androgenetic complete
hydatidiform moles, an abnormality of the trophoblast proliferation, in which the total genome of the fetus is paternally derived (161). Therefore, p57KIP2 has been shown to be a highly
sensitive marker for the differential diagnosis of complete from
partial hydatidiform mole (191-197).
Evidence supports a role for p57KIP2 in cardiovascular pathology. The expression of p57 KIP2 is increased, whereas
p21CIP1/WAF1 and p27KIP1 decline in both acute and end-stage
heart failure, reversing to the fetal pattern of expression (198).
A microsatellite polymorphism, GTn repeat, positioned in the
promoter region of p57KIP2 is related with atherosclerosis and
myocardial infarction (199). The presence of the lower repeats
was significantly more frequent among healthy individuals.
Longer GTn repeats may lead to decreased transcription of
p57KIP2, conferring increased susceptibility to atherosclerosis.
Forced expression of p57KIP2 in cardiomyocytes from transgenic mice exerts a protective role from ischemia-reperfusion injury, possibly via the suppression of the JNK/SAPK pathway
(200). p57KIP2 and p27KIP1 are decreased in damaged podocytes from patients with focal segmental glomerulosclerosis
in comparison with controls (201). This finding is in agreement
with previous studies in experimental models in mice and rat
showing that p57KIP2 is suppressed in glomerular diseases
(160). Of note, p57KIP2 downregulation is accompanied by a
similar decrease in cyclin D3 and increase of cyclin D1 (160,
202). p57KIP2 seems to be involved in the pathogenesis of
autosomal dominant polycystic kidney disease (203). Focal
hyperinsulinism is caused by the absence of the maternal 11p
chromosome (204). The fact that p57KIP2 is lost, whereas IGF2
is up-regulated in tissue specimens from patients with focal
hyperinsulinism compared with controls, may explain the
increased β-cell proliferation in focal hyperinsulinism (205).
Role of p57KIP2 in Carcinogenesis
Studies in Mice and Cell Lines
Takahashi and colleagues (130) did not detect the development of spontaneous tumors during a 5-month observation period of p57KIP2 null mice. However, in p57KIP2−/− mice, 6
months postgrafting, the prostate grafted under the kidney
capsule of athymic mice developed prostatic intraepithelial
neoplasia, a precursor to prostatic cancer (206). Similarly,
p21CIP1/WAF1−/− mice did not develop tumors until the 7th
month of age, whereas after 16 months they were malignant
prone (207). p27 KIP1−/− mice exhibit an increased risk of
pituitary tumorigenesis (137-139).
p57 KIP2 is down-regulated during immortalization of
cultured human mammary epithelial cells (HMEC; ref. 208).
The HMECs undergoing the immortal conversion initially lost
the p57KIP2 maternal allele, associated with the upregulation of
the previously silent allele; however, after adoption of the fully
immortal phenotype, the remaining allele was also downregulated, but not lost. Ectopic expression of p57KIP2 in Ewing
cells induces G1 arrest (21). p57KIP2−/− P-mouse embryo fibroblasts (P signifies parthenogenetic, exclusively comprising the
maternal genome) exhibit increased proliferation in comparison
with P-mouse embryo fibroblasts, where p57KIP2 is intact
(209). We showed that restoration of p57KIP2 levels in A549
restrains cell cycle proliferation, without any significant effect
on apoptosis (59). Similarly, exogenous expression of p57KIP2
in leukemia cells suppresses cell growth (210). Moreover,
p57KIP2 induces apoptosis only in leukemia cell lines with
methylated p57KIP2. p57KIP2-induced expression leads to the
adoption of the senescence phenotype in astrocytoma cell lines
and PPC-1 as mentioned earlier (126, 127). Overexpression of
p57KIP2 reduces the invasiveness of U373 human malignant
glioma cells independent of the extracellular matrix (211).
p57KIP2 Is Frequently Down-regulated in Human Cancers
through Several Mechanisms
p57KIP2 is frequently down-regulated both transcriptionally
and translationally in many human cancers, and its decreased
expression is correlated with aggressiveness in several
malignancies (Table 1; refs. 15, 16, 58, 59, 80, 81, 88, 126,
212-249). Two studies examining the p57KIP2 status in Wilms'
tumor, show that p57KIP2 loss of heterozygosity was associated
with reactivation of the silent allele (loss of imprinting), possibly reflecting the activation of a homeostatic feedback mechanism to prevent cell growth, similar with the p57 K I P2
expression pattern in the immortalization of HMECs (208,
215, 216). Similarly, the increased immunostaining of
p57KIP2 in esophageal squamous cell carcinoma and its positive
association with cyclin E and Ki-67 may reflect the activation
of a feedback mechanism to limit the increased proliferation
(246). In the same manner, in colorectal carcinogenesis
p57KIP2 levels increase significantly from normal mucosa to adenomas and ultimately decrease in primary carcinoma (248).
Downregulation of p57KIP2 is inversely correlated with proliferation in non-small cell lung carcinoma (59), in pancreatic adenocarcinoma (230), in hepatocellular carcinoma (234), in
extrahepatic bile duct carcinoma, and intrahepatic cholangiocellular carcinoma (237). Diminished expression of p57KIP2
predicts poor prognosis in oral squamous cell carcinoma
(225), in laryngeal squamous cell carcinoma (226), in hepatocellular carcinoma (234, 235), and in malignant ovarian tumors
(242). Recently, Yang and colleagues (88) provided evidence
that decreased p57KIP2 expression is related with poor outcome
in breast cancer. The fact that we have not observed any association between p57KIP2 or p27KIP1 immunostaining status, respectively, and patient stage in non-small cell lung carcinoma
suggests a relatively early inactivation of both KIP members in
the development of this type of cancer (59).
The above data, showing that p57KIP2 is increased in the initial stages of cancer followed by a gradual decrease as malignancy progresses, imply that a selective pressure leading to its
loss takes place (59, 208, 246, 248). As we have previously
shown, the DNA damage response (DDR) pathway, which is
also activated from the earliest stages of cancer (250, 251),
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seems to follow the same fate (252). Having in mind that
p57 KIP2 is a target of p73β (90) and that DDR regulates
p73β, as we have recently shown (253), it is tempting to speculate that p57KIP2 could represent an additional downstream
DDR effector. Such a scenario should be further validated.
No mutations of p57KIP2 have been found in all cancer specimens analyzed so far (Table 1). In accordance with p57KIP2,
p21CIP1/WAF1 and p27KIP1 are rarely mutated in human cancers
(96, 113). Therefore, other mechanisms are implicated in
p57KIP2 downregulation in human cancers (Table 1). Our analysis on 70 matched normal tumor specimens from patients with
non-small cell lung carcinoma revealed that multiple mechanisms lead to p57KIP2 downregulation in lung cancer (59). The
majority of cases had decreased expression of p57KIP2, which
was strongly associated with increased SKP2 levels and reduced transcriptional levels of p57KIP2. Increased methylation
of p57KIP2 promoter and loss of heterozygosity were correlated
with p57KIP2 mRNA downregulation. Aberrant methylation
and histone modifications in the p57KIP2 locus seem to be a
crucial mechanism for the inactivation of p57KIP2 in common
malignancies (16). The reactivation of the p57KIP2 gene after
treatment with demethylating agents and histone deacetylase
inhibitor in many cancer cell lines denotes the significance of
the epigenetic mechanisms in p57KIP2-downregulation in several human cancers (16, 59, 86, 89, 210, 223, 241, 249, 254-256).
We showed that treatment of the A549 cell line with 5′-azacytidine, a demethylating agent, up-regulates p57KIP2 mRNA levels significantly, whereas the protein levels do not increase in
a significant manner (59). Only demethylation along with SKP2
siRNA-silencing restored p57KIP2 protein levels in A549 cells.
Interestingly, in our study, a subset of cases with increased
p57KIP2 mRNA exhibited decreased p57KIP2 protein levels possibly because of the increased SKP2 levels. Therefore, it is essential to examine the p57KIP2 mRNA levels along with its
protein status in order to clarify cumulatively the end effect
from the demethylating agents on gene transcription and from
p57KIP2 protein degradation in human cancer. It is possible that
increased p57KIP2 mRNA expression, observed in some malignancies, may be counterbalanced by elevated p57KIP2 protein
degradation (Table 1). In view of emerging molecular therapeutic approaches, aiming to restore the CIP/KIP activity in various malignancies, such collective information is crucial for
their success (257).
According to the imprinting pattern of LIT1 and p57KIP2, the
expression status of these genes is inversely correlated. However, we did not observe a strong inverse relation between LIT1
and p57KIP2 expression, which is in accordance with the findings of Hoffmann and colleagues (249) in bladder carcinoma,
Sato and colleagues (247) in pancreatic ductal neoplasms, and
Nakano and colleagues (258) in several colorectal cancer cell
lines. It is possible that LIT1 cooperates with several elements
lying in the 11p15.5 region, in order to promote the proper imprinting of p57KIP2. The absence of a significant relationship
between p57KIP2 and LIT1 expressional status may be due to
the disruption of the integrity of the 11p15.5 region due to loss
of heterozygosity, which is a frequent event in this chromosomal region in many cancers (259). Alternatively, this mechanism
may be tissue specific. Soejima and colleagues (260) found that
diminution of p57KIP2 in several human esophageal cancer cell
lines was associated with the epigenetic status of LIT1 locus
and not of its own promoter.
A functional link between miRNA-25, miRNA-221 and
miRNA-222, and p57KIP2 mRNA levels, mediating suppression
of the latter, has been recently shown in HeLa; in MCF7 (human breast cancer cell line); in the human gastric cancer cell
lines SNU-638, AGS, and MKN-28 (81); in K562 (human leukemic cell line); and in the T98G (human glioblastoma) cell
line (82), as well as in vivo in human gastric and hepatocellular
carcinomas (80, 81).
It seems that p57KIP2 has a more clear-cut oncosuppressor
activity in comparison with the other members of CIP/KIP family so far. p57KIP2 is frequently targeted in most cancers supporting its tumor-suppressor activity, however deductions
about p57KIP2 function can be made only in the tissue context
examined. Indeed, p21CIP1/WAF1 has both an oncogenic and a
tumor-suppressor activity dependent on the tissue studied
(96). Moreover, p27KIP1 harbors an oncogenic function when
it is localized in the cytoplasm of many common tumors
(119). The cytoplasmic localization of p57KIP2 in some cancers
may introduce an oncogene-like behavior. However, the fact
that cytoplasmic mouse p57KIP2 translocates LIMK1 from the
cytoplasm to the nucleus, and that the elevated cytoplasmic
LIMK1 promotes cancer invasion (261), supports a tumor-suppressor activity for cytoplasmic p57KIP2, although more studies
are needed to clarify this issue.
The examination of the unique central domain of p57KIP2,
PAPA region, by Tokino and colleagues (15) resulted in an association of specific PAPA polymorphisms with breast cancer risk.
However, in a subsequent analysis in a larger cohort by Li and
colleagues (262), this correlation was not confirmed. Therefore,
this issue remains unresolved and requires further investigation.
Conclusion
p57KIP2 has a distinct role in embryogenesis among CIP/KIP
members. The increased mortality of p57KIP2 knockout mice
denotes its impact on tissue development. The absence of mutations of p57KIP2 in all cancers studied so far implies the importance of the integrity of this gene for cell viability. The
participation of p57KIP2 in cell cycle arrest and the identification of putative novel functions in endoreduplication, mitotic
exit, apoptosis, senescence, and cytoskeletal organization highlight its significance in the context of its frequent downregulation in many human cancers. The effort to unravel the
biology of p57KIP2 has already provided a useful diagnostic
marker in the differential diagnosis of complete from partial
hydatidiform moles. In the future, the putative antitumor
functions of p57KIP2 may be exploited to design novel therapeutic agents for BWS and several common malignancies.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Notes Added in Proof
The following publications have come to our attention since
the review entered the proof preparation.
1. Vlachos and Joseph reported that human p57KIP2 interacts
in the cytoplasm with LIMK-1 enhancing its kinase activity,
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1914 Pateras et al.
resulting in the inactivation of cofilin. They showed that the
cytoplasmic localization of p57KIP2 negatively affects cell
mobility, reinforcing the oncosuppressor activity of p57KIP2
in the cytoplasm (263).
2. Mascarenhas and colleagues depicted the involvement
of p57KIP2 in hematopoietic development (264).
24. Russo AA, Jeffrey PD, Patten AK, Massague J, Pavletich NP. Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin ACdk2 complex. Nature 1996;382:325–31.
25. Wright PE, Dyson HJ. Intrinsically unstructured proteins: re-assessing the
protein structure-function paradigm. J Mol Biol 1999;293:321–31.
26. Brown CJ, Takayama S, Campen AM, et al. Evolutionary rate heterogeneity
in proteins with long disordered regions. J Mol Evol 2002;55:104–10.
27. Dunker AK, Brown CJ, Lawson JD, Iakoucheva LM, Obradovic Z. Intrinsic
disorder and protein function. Biochemistry 2002;41:6573–82.
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1919
Published OnlineFirst November 24, 2009; DOI: 10.1158/1541-7786.MCR-09-0317
p57KIP2: ''Kip''ing the Cell under Control
Ioannis S. Pateras, Kalliopi Apostolopoulou, Katerina Niforou, et al.
Mol Cancer Res 2009;7:1902-1919. Published OnlineFirst November 24, 2009.
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