Cancer Biology Program, Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
* Authors for correspondence (e-mail: klu{at}caregroup.harvard.edu; gwulf{at}caregroup.harvard.edu)
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Summary |
---|
Key words: Phosphorylation, Prolyl-isomerase, Pin1, Post-phosphorylation regulation, Signal transduction, Oncogenesis
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Introduction |
---|
Ser/Thr-Pro motifs are the major phosphorylation sites for a large
superfamily of `proline-directed' kinases, including cyclin-dependent kinases
(CDKs), mitogen-activated protein kinases (MAPKs) and glycogen synthase kinase
3ß (GSK-3ß), and conversely they are dephosphorylated by Ser/Thr
phosphatases, including PP2A, FCP1 and calcineurin
(Lu, K. P. et al., 2002b).
Furthermore, MAPK ERK2 and CDK2, as well as the Ser/Thr phosphatase PP2A, are
conformation specific, preferentially phosphorylating/dephosphorylating the
trans isomer (Brown et al.,
1999
; Weiwad et al.,
2000
; Zhou et al.,
2000
). Ser/Thr phosphorylation has for a long time been believed
to regulate the function of proteins by altering their conformations; however,
little is known about the actual conformational changes and their importance.
The identification and characterization of a peptidyl-prolyl cis/trans
isomerase (PPIase), Pin1, has led to the discovery of a novel
post-phosphorylation regulatory mechanism
(Lu et al., 1996
;
Ranganathan et al., 1997
;
Yaffe et al., 1997
). Pin1
binds to and isomerizes the peptidyl-prolyl bond in specific phosphorylated
Ser/Thr-Pro motifs and thereby induces conformational changes in its target
proteins (Albert et al., 1999
;
Arevalo-Rodriguez et al., 2000
;
Hsu et al., 2001
;
Kops et al., 2002
;
Liou et al., 2002
;
Lu et al., 1999a
;
Lu et al., 1999b
;
Ryo et al., 2002
;
Ryo et al., 2001
;
Shen et al., 1998
;
Stukenberg and Kirschner,
2001
; Wu et al.,
2000
; Wulf et al.,
2002
; Wulf et al.,
2001
; Yaffe et al.,
1997
; Zacchi et al.,
2002
; Zheng et al.,
2002
; Zhou et al.,
2000
). These conformational changes can have profound effects on
the function of Pin1 substrates, modulating their activity, phosphorylation
status, protein-protein interactions, subcellular localization and stability
(Fig. 1). For example, Pin1 can
bind to and induce conformational changes in the mitotic phosphatase Cdc25C
and the microtubule-binding protein tau, after they have been phosphorylated
on specific Ser/Thr-Pro motifs. Such conformational changes can directly
inhibit the ability of phosphorylated Cdc25C to dephosphorylate and activate
Cdc2 (Shen et al., 1998
;
Stukenberg and Kirschner,
2001
; Zhou et al.,
2000
), or restore the ability of phosphorylated tau to promote
microtubule assembly (Lu et al.,
1999a
). Furthermore, such conformational changes can also regulate
the dephosphorylation of Cdc25C and tau because phosphatases such as PP2A
dephosphorylate only the trans isoform of phosphorylated Ser/Thr-Pro motifs
(Zhou et al., 2000
). Thus,
phosphorylation-dependent prolyl isomerization is a new post-phosphorylation
signaling mechanism.
|
Pin1 was originally identified in a yeast two-hybrid screen as a human
protein that interacts physically and functionally with a mitotic kinase and
was the first peptidyl-prolyl cis/trans isomerase (PPIase) shown to be
essential for cell division in yeast and human cells
(Lu et al., 1996). Pin1
homologues are highly conserved in eukaryotes
(Huang et al., 2001
;
Landrieu et al., 2000
;
Metzner et al., 2001
;
Yao et al., 2001
;
Zhou et al., 1999
), and the
budding yeast homologue, Ess1p/Ptrf1p, was isolated a long time ago but did
not have any previously known activity
(Hanes et al., 1989
;
Hani et al., 1995
). With the
exception of the plant enzymes, which appear to contain only PPIase domains,
most other Pin1-type PPIases also contain an N-terminal WW domain. The
function of the WW domain is to target the enzyme to its substrates, where the
PPIase domain is both sufficient and necessary to catalyze the conformational
change and to carry out the essential function of this enzyme. Depletion of
Pin1 causes mitotic arrest and apoptosis in budding yeast and tumor cell lines
(Lu et al., 1996
), and Pin1 is
required for the DNA replication checkpoint and G2/M transition in
Xenopus extracts (Winkler et
al., 2000
). Pin1 has been shown to be involved in the regulation
of many other cellular events, such as cell cycle progression, transcriptional
regulation and cell proliferation and differentiation
(Albert et al., 1999
;
Arevalo-Rodriguez et al., 2000
;
Crenshaw et al., 1998
;
Gerez et al., 2000
;
Hani et al., 1999
;
Hsu et al., 2001
;
Kamimoto et al., 2001
;
Lavoie et al., 2001
;
Liou et al., 2002
;
Liu et al., 2001
;
Messenger et al., 2002
;
Morris et al., 1999
;
Pathan et al., 2001
;
Patra et al., 1999
;
Rippmann et al., 2000
;
Ryo et al., 2002
;
Ryo et al., 2001
;
Shen et al., 1998
;
Wu et al., 2000
;
Wulf et al., 2001
).
Furthermore, it is involved in the DNA damage response, regulating p53
function (Wulf et al., 2002
;
Zacchi et al., 2002
;
Zheng et al., 2002
).
Moreover, it is also involved in Alzheimer's disease
(Lu et al., 1999a
;
Zhou et al., 2000
) and cancer
(Liou et al., 2002
;
Ryo et al., 2002
;
Ryo et al., 2001
;
Wulf et al., 2001
).
Here we review recent studies demonstrating the role of Pin1 in cell growth
control and oncogenesis and discuss the feasibility of Pin1 as a potential
therapeutic target for anti-cancer treatment. Comprehensive recent reviews on
function and regulation of Pin1 (Lu, K. P.
et al., 2002b; Zhou et al.,
1999
), as well as its specific role in transcription
(Shaw, 2002
) and in
Alzheimer's disease (Lu, K. P. et al.,
2002a
), are available elsewhere.
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Regulation of cyclin D1 expression |
---|
|
Elevated Pin1 levels in breast cancer significantly correlate with cyclin
D1 overexpression (Ryo et al.,
2002; Ryo et al.,
2001
; Wulf et al.,
2001
). In fact, we have found that Pin1 levels in cyclin D1
overexpressing tumors are on average about twice as high as those in
cyclin-D1-negative tumors. This is significant given that cyclin D1 is an
essential downstream target for mammary tumorigenesis. Cyclin D1 is
overexpressed in about half of breast cancer patients
(Bartkova et al., 1994
;
Gillett et al., 1994
).
Overexpression of cyclin D1 contributes to cell transformation
(Alt et al., 2000
;
Hinds et al., 1994
),
inhibition of cyclin D1 expression by antisense expression causes growth
arrest in tumor (Arber et al.,
1997
; Driscoll et al.,
1997
; Kornmann et al.,
1998
; Schrump et al.,
1996
) and disruption of the cyclin D1 gene in mice completely
suppresses the ability of Ha-Ras or Her2/Neu to induce tumor development in
mammary glands (Yu et al.,
2001
). In breast cancer tissues, Her2/Neu overexpression
correlates with Pin1 overexpression, although this correlation did not reach
statistical significance, probably because of the small number of
Her2/Neu-positive patients in the study
(Wulf et al., 2001
). It is of
interest, though, that Pin1 levels were 1.7-2 times higher in patients who are
either Her2/Neu positive, or negative for estrogen receptor expression
(Wulf et al., 2001
). Further
studies in larger cohorts may clarify the relationship between Pin1 expression
and these unfavorable biochemical markers, and establish whether Pin1
expression would be a useful additional marker for breast cancer
prognosis.
![]() |
Cooperation with the Ras/AP-1 signaling pathway |
---|
We have found that Pin1 not only binds phosphorylated Jun but also
increases its ability to activate the cyclin D1 promoter in cooperation either
with activated JNK or oncogenic Ha-Ras. In contrast, inhibition of endogenous
Pin1 reduces the transcriptional activity of phosphorylated Jun, indicating
that endogenous Pin1 is also required for optimal activation. Thus, Pin1 is a
potent modulator of phosphorylated Jun in inducing cyclin D1 expression,
presumably by regulating the conformation of the phosphorylated Ser-Pro motifs
in Jun (Wulf et al., 2001).
Jun is basically a positive regulator of cell proliferation
(Behrens et al., 1999
;
Brown et al., 1998
;
Shaulian and Karin, 2001
;
Shaulian and Karin, 2002
),
and the Pin1-induced conformational changes in Jun potentially affect its
ability to form homo- or hetero-dimers and/or its DNA binding activity.
However, further studies are necessary to define the molecular mechanisms by
which Pin1 affects Jun function.
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Activation of the Wnt/ß-catenin pathway |
---|
A differential display screen for genes regulated by Pin1 that compared
inducible Pin1-overexpressing breast cancer MCF-7 cells and control cells
identified 17 known genes (Ryo et al.,
2001). Interestingly, four of the 12 genes whose expression is
upregulated are targets of ß-catenin and its transcriptional partner TCF:
those encoding cyclin D1, Myc, PPAR-delta and fibronectin
(Gradl et al., 1999
;
He et al., 1999
;
He et al., 1998
;
Tetsu and McCormick, 1999
).
Overexpression or depletion of Pin1 in cell lines has been shown to regulate
the stability and subcellular localization of ß-catenin
(Ryo et al., 2001
). In
addition, Pin1 can activate the cyclin D1 promoter not only through AP-1 sites
but also through TCF-binding sites that are present
(Ryo et al., 2001
).
Upregulation of Pin1 in breast cancer strongly correlates with increased
ß-catenin levels in the tumors examined, whereas ß-catenin levels
are decreased in Pin1-knockout mouse tissues
(Ryo et al., 2001
).
How does Pin1 regulate ß-catenin levels? As shown above,
conformational changes caused by Pin1-catalyzed prolyl-isomerization can
affect protein stability, phosphorylation status and protein-protein
interactions (Hsu et al.,
2001; Kops et al.,
2002
; Liou et al.,
2002
; Lu et al.,
1999a
; Lu et al.,
1999b
; Ryo et al.,
2002
; Ryo et al.,
2001
; Shen et al.,
1998
; Stukenberg and
Kirschner, 2001
; Wulf et al.,
2002
; Wulf et al.,
2001
; Yaffe et al.,
1997
; Zacchi et al.,
2002
; Zheng et al.,
2002
; Zhou et al.,
2000
). Pin1 binds exclusively to phosphorylated ß-catenin,
and its binding site has been mapped to the pSer246-Pro motif
(Ryo et al., 2001
). This
motif is located at an exposed loop region between the two helixes at the
third armadillo repeat interface, and it is next to the surface that interacts
with APC in the three-dimensional structure of ß-catenin
(Graham et al., 2000
;
Huber et al., 1997
;
von Kries et al., 2000
). APC
is the shuttling protein that exports nuclear ß-catenin to the cytoplasm
for degradation (Bienz, 2002
;
Henderson, 2000
;
Neufeld et al., 2000
;
Rosin-Arbesfeld et al.,
2000
). Mutations of Phe253 and Phe293 in
ß-catenin abolish its ability to bind to APC
(Graham et al., 2000
;
Huber et al., 1997
;
von Kries et al., 2000
).
Similarly, Pin1 binding and isomerization specifically inhibits the
interaction between ß-catenin and APC, resulting in the nuclear
accumulation and stabilization of ß-catenin. Pin1-dependent
prolyl-isomerization thus appears to be a novel mechanism for the regulation
of ß-cateninAPC interaction. Given the overexpression of Pin1 in
many cancers, this mechanism might up-regulate ß-catenin activity in
tumors such as breast cancer, in which APC and/or ß-catenin mutations are
not common (Ryo et al.,
2001
).
![]() |
Regulation of cyclin D1 protein levels |
---|
![]() |
Regulation of pin1 transcription and function by oncogenic pathways |
---|
In addition to being transcriptionally regulated, Pin1 is also regulated by
post-translational controls. One such regulatory mechanism is phosphorylation.
Phosphorylation of the Pin1 WW domain inhibits its ability to bind target
proteins and regulates the subcellular localization of Pin1
(Lu, P. J. et al., 2002).
Dephosphorylated Pin1 accumulates during the G2/M transition in HeLa cells,
whereas in G1 and S phase phosphorylated Pin1 is predominant
(Lu, P. J. et al., 2002
). In
human breast tumors, the dephosphorylated, and presumably active, form of Pin1
accumulates (Wulf et al.,
2001
). It will be important to identify the specific kinase
responsible because, theoretically, this kinase would be able to inhibit Pin1
function, thereby suppressing its ability to activate oncogenic pathways as
described above. Phosphospecific antibodies will help us to assess more
accurately the ratio of phosphorylated to dephosphorylated Pin1 and may become
an important tool for identifying the kinase/phosphatase activities regulating
the phosphorylation status of Pin1. Finally, Pin1 levels have been shown to be
decreased upon prolonged exposure to the microtubule-targeting drug Taxol,
which can apparently be prevented by some proteasome inhibitors; this suggests
that Pin1 is also subjected to proteolytic regulation
(Basu et al., 2002
). However,
direct evidence for such a regulatory mechanism has not yet been provided.
![]() |
Pin1 overexpression and cell transformation |
---|
Neu or Ras signaling is frequently deregulated in breast cancers, although
mutations and amplifications of these genes are rarely observed
(Andrechek and Muller, 2000;
Harari and Yarden, 2000
).
Transgenic overexpression of MMTV-Ha-Ras or MMTV-Neu potently induces mammary
tumors by stimulating cyclin D1. However, transgenic overexpression of
MMTV-cyclin D1 is much less tumorigenic
(Muller et al., 1988
;
Sinn et al., 1987
;
Wang et al., 1994
). In
addition, constitutive overexpression of cyclin D1 alone cannot transform
MCF-10A cells, nor is it sufficient to prevent G1 arrest induced by EGF
deprivation (Chou et al.,
1999
). These discrepancies could be explained by the findings that
cyclin D1 is regulated not only by transcriptional activation but also by the
post-translational stabilization described above. In contrast to wild-type
cyclin D1, the mutant cyclin D1T286A is stable and functions as a
constitutively active mutant that can potently transform fibroblasts
(Alt et al., 2000
). Both
transcriptional activation and post-translational stabilization of cyclin D1
thus seem to be critical for tumor development induced by Neu/Ras
signaling.
Similarly to cyclin D1, Pin1 is highly overexpressed in the mammary glands
of transgenic mice that overexpress MMTV-Neu or MMTV-Ha-Ras
(Muller et al., 1988;
Ryo et al., 2002
;
Sinn et al., 1987
).
Inhibition of Pin1 by a dominant negative mutant or an antisense construct
dramatically reduces both cell proliferation and the transformation induced by
the Neu and Ras oncogenes. This reduction can be reversed by expression of the
constitutively active cyclin D1 T286A mutant that is resistant to Pin1
inhibition (Ryo et al.,
2002
). These results suggest that cyclin D1 is a specific
downstream target of Pin1 for oncogenesis. Cyclin D1 is overexpressed in 50%
of all breast cancers, but genetic amplification accounts for only 10% of this
overexpression (Sutherland and Musgrove,
2002
). Pin1 therefore probably plays an important role in
maintaining cyclin D1 levels sufficient for transformation of mammary
epithelial cells.
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Regulation of p53 in the DNA damage response |
---|
The physiological consequences of Pin1 loss in normal cells are still
controversial. Zheng et al. (Zheng et
al., 2002) and Wulf et al.
(Wulf et al., 2002
) show that
Pin1 is required for maintaining the DNA-damage cell cycle checkpoint by
inducing the cell cycle inhibitor p21, which will protect cells from DNA
damage-induced cell death (Wulf et al.,
2002
; Zheng et al.,
2002
). In contrast, Zacchi et al. claim that Pin1 accelerates
apoptosis by enhancing pro-apoptotic genes downstream of p53, such as Bax and
DR2/Killer (Zacchi et al.,
2002
). This discrepancy may reflect the fact that p53 induces sets
of genes required for cell cycle arrest and apoptosis, depending on the
cellular context and intensity and timing of the respective DNA damage
(Colman et al., 2000
;
Lakin and Jackson, 1999
;
Meek, 1999
;
Ryan et al., 2001
;
Taylor and Stark, 2001
;
Wahl and Carr, 2001
). Careful
in vivo analysis of the effects of different types of genotoxic insult may
clarify whether Pin1-mediated prolyl isomerization of p53 directs the cells in
a given cell towards apoptosis or towards cell cycle arrest.
These results are initially counterintuitive: why would a protein that
amplifies oncogenic signals also activate a tumor suppressor gene?
Proline-directed phosphorylation plays an important role in both the promotion
and suppression of oncogenesis, and therefore Pin1 is likely to be involved in
both processes. It has been well established that many proteins are involved
in both processes. For example, transcription factors such as Myc and E2F
family members participate in a complex signaling network that regulates cell
growth, differentiation, cell survival and apoptosis in non-malignant cells.
Only in a permissive environment will overexpressed or mutated forms of these
proteins contribute to carcinogenesis
(Oster et al., 2002;
Trimarchi and Lees, 2002
;
Zhou and Hurlin, 2001
).
Therefore, it may be important to distinguish the physiological function of
Pin1 in normal cells from its pathological role in cancers where Pin1 is
deregulated. It is likely that, under physiological conditions in normal
cells, Pin1-mediated p53 regulation is important for cell cycle checkpoint
regulation and the maintenance of genomic stability. In cancer cells, however,
this mechanism may be defective because oncogenic signalling pathways induced
by Pin1 overexpression may override the DNA damage repair mechanisms and/or
because p53 is absent or mutated in many cancer cell types. Interestingly,
Pin1 can also stabilize p53 mutants with the same efficacy as the wild-type
protein (G.W. and K.P.L., unpublished results). Since a cellular environment
in which Myc and/or Ras expression is deregulated can favor the selection of
p53 mutations (Chikatsu et al.,
2002
) and since some p53 mutants function as dominant negative
mutants (de Vries et al.,
2002
; Monti et al.,
2002
), Pin1 overexpression in the context of a mutated
p53 gene might even contribute to genomic instability in cancer
cells. However, further studies are needed to define the physiological and
pathological roles of Pin1-mediated p53 regulation.
![]() |
Is Pin1 an oncogene or a catalyst for oncogenic activation? |
---|
Pin1 thus functions at multiple steps in oncogenic signaling pathways as an
`oncogenic catalyst' (Fig. 2).
It collaborates with Ras/JNK signaling to increase the transcriptional
activity of Jun towards cyclin D1 (Wulf
et al., 2001). It also activates ß-catenin, which can induce
the transcription of the cyclin D1 gene, Jun and Myc
(Behrens et al., 1996
;
He et al., 1998
;
Mann et al., 1999
;
Molenaar et al., 1996
;
Ryo et al., 2002
;
Tetsu and McCormick, 1999
).
In addition, Myc can enhance cyclin D1 function by inducing Cdk4 expression
(Hermeking et al., 2000
) and
also directly induce E2F family genes
(Leone et al., 2000
;
Sears et al., 1997
). These
molecules act synergistically to regulate cyclin D1 and E2F function. Finally,
Pin1 itself is further upregulated by E2F activation in a positive
feedback loop (Ryo et al.,
2002
) (Fig. 2). The
amplification of this positive feedback pathway may play a role in aberrant
cell proliferation and oncogenesis.
|
![]() |
Therapeutic implications |
---|
The feasibility of therapeutic inhibition of Pin1 has not yet been
explored. In contrast to cyclophilins and FK506-binding proteins, where highly
specific inhibitors are well characterized and widely used clinically
(Fischer, 1994;
Hunter, 1998
;
Schreiber, 1991
), the only
known Pin1 inhibitor is Juglone (Hennig et
al., 1998
). Juglone covalently inactivates a unique cysteine
residue in the active site of Pin1-type and parvulin-type isomerases. Juglone
has some anti-cancer activity and has been used as a Pin1 inhibitor in several
studies in cells (Chao et al.,
2001
, He et al.,
2001
; Rippmann et al.,
2000
). However, given that Juglone potently inhibits many other
proteins and enzymes (Chao et al.,
2001
; Duhaiman,
1996
; Munday and Munday,
2000
; Muto et al.,
1987
), it is unlikely to be Pin1 specific in the cell. Therefore,
there is a need for the development of Pin1-specific inhibitors. In addition
to providing powerful tools for dissecting Pin1 function in vivo, such
Pin1-specific inhibitors may open a new avenue for anticancer treatment. They
may themselves be highly effective anticancer drugs or become valuable
adjuncts to established chemotherapeutic regimen.
![]() |
Conclusions and perspectives |
---|
![]() |
Acknowledgments |
---|
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