ARTICLE
Auteur(s) : Audrey Petitjean1, Pierre
Hainaut1, Claude Caron de
Fromentel2
1International Agency for Research on Cancer, 150
cours Albert-Thomas, 69372 Lyon Cedex 08, France
2Inserm Unit 590, Université Lyon 1, 69000 Lyon France,
Bât. Cheney A, Centre Léon Bérard, 28 rue Laennec, 69373 Lyon Cedex
08, France
The TP53 gene (l7p13) was discovered in 1979, and gained its status
as one of the most important cancer genes in the late eighties,
when it became evident that about half of all cancers contained
inactivated TP53 alleles. In 1997, two genes homologous to TP53
were discovered almost simultaneously [1, 2]. These genes are now
commonly referred to as TP63 (3q27.29) and TP73 (1p36), and from
this discovery has emerged the notion of “TP53 family”.One of the
differences between TP63, TP73 and TP53 resides in their
transcriptional regulation and expression profiles. In
physiological conditions, TP63 and TP73 expression is tissue- and
cell-type specific [3, 4], whereas TP53 expression is ubiquitous.
This difference reflects functional specificities, since p63
protein is a tissue-specific differentiation regulator [5].
Moreover, in human, germline mutations in TP63 gene are linked to
some developmental syndrome characterized by limb abnormalities,
ectodermal dysplasia and facial clefts [6]. In contrast, p53 is
known to exert multiple functions in stress response and DNA repair
in all cell types. TP73 appears to have a somewhat hybrid profile
between the one of TP53 and TP63, since p73 protein is detectable
in a more tissue-restricted manner than p53, but in a larger range
of tissues than p63, until now.Phylogenic studies have allowed
determining that the three members of the family probably derive
from a common ancestor, which may correspond to the “TP53-like”
gene identified in C. elegans. This unique ancestor probably
underwent two successive duplications, the first one generating the
TP63 and TP73 sequences, and the second one leading to TP53 [7, 8].
These events took place relatively late in evolution and, as a
result, only vertebrates harbour the three distinct genes. From
this, we can suppose proteins of the “p53 family” may have some
common properties. In fact, p73 has long been recognized as a
stress response protein, due to its capacity to associate with
stress response kinases such as c-Abl, to undergo phosphorylation
and to mediate apoptosis in response to DNA damage [9-11].
Moreover, evidence is accumulating that p63 may also play an
important role in response to various types of stress, in synergy
with p53 [12], as well as in a p53-independent manner [13, 14]. In
this review, we summarize the structural and functional
characteristics of p63, and we look over the evidence on its role
in cell cycle arrest and apoptosis in response to stress signals.
Finally, we discuss the relevance of this information to cancer,
focusing on the possible role of some p63 isoforms as “true
oncogenes” in several types of cancer.
Structural properties of p53 family members
p53, p63 and p73 present a typical structure of transcription
factor, with a transactivation domain at the N-terminus, a
DNA-binding domain (DBD) in the central part of the molecule and an
oligomerisation domain at the C-terminus ( (figure 1) ). The homology
between the three proteins is not equally distributed along the
molecules, with the DBD sharing the greatest homology (over 60% of
conservation between the three family members). All the residues
that have been identified in p53 as playing an important role in
the folding of the DNA-binding domain and in the contact with DNA
are well conserved in p63 and in p73, suggesting that the overall
shape of this domain is similar in the three family members. This
similarity accounts for the capacity of p63 to bind to similar DNA
consensus sequences as those recognized by p53 and p73. In
contrast, the N- and C-terminal regions of p63 show similarities
with the corresponding domains of p73, but are quite divergent of
those of p53 (homology around 25 and 37%, respectively). In
particular, the N- and C-terminal regions of p53 contain a series
of well defined phosphorylation and acetylation sites and none of
them is conserved in the p63 structure.
The three family members are expressed as multiple isoforms.
They all conserve the DNA-binding domain, but may differ in their
N- and C-terminal regions ( (figure 1) ). The TA
(transactivation) isoform, generated from the promoter P1, retains
the full transactivation domain. In the case of p63, an alternative
version of the TA isoform has been found in the mouse (TAp63*), but
not in humans. This variant contains 39 additional amino acids
resulting from the use of an in-frame AUG located upstream of the
major initiation site [15].
The ΔNp63 isoform is produced by the use of an internal
promoter, P2, and an additional exon (exon 3’), both located in
intron 3. The resulting protein lacks the sequence encoded by exons
2 and 3 (transactivation domain), but contains a small specific
N-terminus [15]. In the case of p73, truncated isoforms are
generated through transcription from an internal promoter in intron
3 in a manner similar to p63, and by alternative splicing that
skips exon 2, 3 or both, or adds intron 3 (leading to the Δex2,
Δex3, Δex2/3 and ΔN’ isoforms respectively) [16, 17]. The p53
isoforms are less well characterized and have been described only
recently. The ΔN/Δ40 isoform results from an internal translation
at codon 40 [18, 19]. The other isoform, Δ133p53, is generated by
an alternative promoter in intron 4 [20].
Independently of their N-terminal status, p63 and p73 exist as a
variety of C-terminal splicing variants. Three different forms have
been identified for p63: α, β and γ ( (figure 1) ). The situation
is more complex for p73 with six different forms: α, β, γ, δ, ε and
ζ. The p63α and p73α isoforms contain a sterile alpha motif (SAM),
a protein-protein interaction domain found in a wide variety of
proteins implicated in development, and a “post-SAM” domain.
Concerning p63α, the “post-SAM” domain is able to bind to the TA
region [21]. For p53, three C-terminal isoforms have been recently
described. They are also called α, β and γ forms by analogy, but do
not correspond to the ones of p63 and p73 [20].
Expression of p63 isoforms
TP63 expression in normal adult tissues is restricted to the basal
compartment of stratified epithelia from prostate, skin,
oesophagus, cervix and vagina and to certain populations of basal
cells in the glandular structures of prostate, breast and bronchi
[3]. This makes it a very good marker of myoepithelial cells in
breast or basal cells in prostate. The expression profile is not
the same for all the isoforms. The most abundant isoform expressed
in basal cells of the epithelium is ΔNp63α. Which cells within the
epithelium express TA isoforms remains an open question. On one
hand, there is evidence that TA isoforms become expressed in
terminally differentiated stages, an observation compatible with
their expected function as growth suppressors and effectors of
differentiation [22]. On the other hand, recent studies also show
that TA isoforms are present during development in basal, stem-like
cells, suggesting that they play a role in the early stages of cell
commitment into specific epithelial lineages [23, 24].
As mentioned above, the expression of TA and ΔN isoforms is
under the control of two promoters, P1 and P2, respectively.
Although the regulation of these promoters is not fully elucidated
yet, some binding sites have been identified. Several putative E2F
binding sites were found in P1 and P2, but experimentally, E2F1
doesn’t activate TP63 promoters. The P2 promoter also contains a
p53 responsive element (RE), but the effect of p53 on ΔNp63
expression is still controversial. Harmes et al. [25] showed an
activation by p53 and an inhibition by ΔNp63 itself, whereas
Dobbelstein’s group reported that ΔNp63 expression is inhibited by
p53 [26]. Nevertheless, some observations are in favour of this
latter [14].
Biochemical and functional properties of p63 isoforms
The exact functional characteristics of each p63 isoforms, and
mostly their physiological relevance, are matter of debate. A
survey of the literature points to a lack of systematic studies
comparing the properties of each isoforms when expressed into the
same cellular model. In the section below, we provide a critical
assessment of the data available. However, better elucidation of
the functions of p63 isoforms awaits more sophisticated studies,
e.g. using recombinant mice expressing exclusively one single p63
isoform.
TAp63 activity
In agreement with their structure of transcription factor, TAp63
isoforms are able to form oligomers through their C-terminal domain
and to transactivate some genes (table 1)( Table
1 ). Because of the high homology between p53- and p63-DBD,
the effect of p63 has been particularly studied on p53-responsive
elements. Thus, the first p63-target genes described correspond to
some p53-target genes involved in cell cycle arrest, sometimes to a
higher extend than p53 itself. Moreover, for a short time, p63 also
appears able to modulate the expression of some genes involved in
apoptosis, cell proliferation and inhibition of tumour progression.
In addition, TAp63 can regulate the expression of more specific
genes (i.e. not regulated by p53), whose expression products are
involved in development, epithelial terminal differentiation and
cell adhesion. References to the articles reporting the regulation
by p63 are given in the table 1.
The transactivation effectiveness on target genes is modulated
by the C-terminal end of each TAp63 isoform. Indeed, TAp63γ appears
to mimic p53 effects on genes involved in cell cycle arrest or
apoptosis, whereas TAp63α has been more linked to development and
terminal differentiation. Nevertheless, while the γ isoform is also
expressed in some embryonic tissues [27], its ability to modulate
the expression of genes involved in developmental processes is
actually not known.
The reason why some genes can be transactivated by p63 but not
by p53 is not well understood so far. A piece of evidence has been
recently provided by the examination of the responsive element (RE)
found in p53- and p63-target genes. The well described consensus
sequence of p53-RE is 5’PuPuPuC(A/T)(T/A)GPyPyPy3’, where Pu is
adenosine or guanine base, and Py is cytosine or thymine base [28].
Osada et al. [29] have recently described that, if both p63 and p53
bind the following RE, 5’PuPuPuCATGPyPyPy3’, only p63 can
efficiently bind the sequence 5’PuPuPuCGTGPyPyPy3’, thus
explaining its specificity towards some genes, such as EVPL and
SMARCD3. Another explanation for p63 (and p73) transactivation
specificity could lie in the presence of both a canonical
p53-responsive element and a GC-rich sequence which serves as an
enhancer. Such sequences have been identified in the promoter of
WNT4 gene [30]. Of course, the responsive elements regulated by p63
proteins clearly have to be still studied and defined. However,
taken together, the data available so far indicate that the notion
of “p53-target genes” needs to be revisited. First, a part of the
previously described “p53-target genes” are more obvious p63 and/or
p73-target genes. Second, additional categories are now emerging,
such as “p53 family-target genes”, “p63- and p73-target genes”,
“p63 specific-target genes” or “p53 specific-target genes”
categories.
Table 1 TAp63-target genes
|
Biological process
|
TAp63-target gene
|
Effect
|
Reference
|
Gene also regulated by
|
|
p53
|
p73
|
|
Cell cycle control
|
14-3-3σ
|
+
|
[83]
|
yes
|
yes
|
|
GADD45
|
+
|
[46]
|
yes
|
yes
|
|
p57KIP2
|
-
|
[84]
|
yes
|
yes
|
|
WAF1
|
+
|
[15]
|
yes
|
yes
|
|
Cell proliferation
|
ADAc
|
+
|
[85]
|
no
|
yes
|
|
EGFR
|
-
|
[86]
|
yes
|
?
|
|
Epithelial differentiation
|
INVOLUCRIN
|
+
|
[87]
|
no
|
yes
|
|
LORICRIN
|
+
|
[87]
|
no
|
yes
|
|
VDR
|
+
|
[88]
|
no
|
?
|
|
Development
|
EphA2a,b
|
+
|
[89]
|
yes
|
yes
|
|
JAG1
|
+
|
[90]
|
no
|
yes
|
|
JAG2
|
+
|
[90]
|
no
|
yes
|
|
WNT4
|
+
|
[30]
|
no
|
yes
|
|
Cell adhesion
|
BPAG-1e
|
+
|
[91]
|
no
|
no
|
|
EVPL
|
+
|
[29]
|
no
|
?
|
|
INTA3
|
+
|
[92]
|
?
|
?
|
|
PERPa
|
+
|
[93]
|
yes
|
?
|
|
Apoptosis
|
BAX
|
+
|
[83]
|
yes
|
yes
|
|
FAS
|
+
|
[13]
|
yes
|
yes
|
|
FDXR
|
+
|
[60]
|
yes
|
yes
|
|
IGF-IR
|
-
|
[94]
|
yes
|
yes
|
|
PIG-3
|
+
|
[45]
|
yes
|
yes
|
|
PUMA
|
+
|
[45]
|
yes
|
yes
|
|
REDD1c
|
+
|
[61]
|
yes
|
?
|
|
Tumour progression
|
HSP70
|
-
|
[95]
|
yes
|
?
|
|
MASPIN
|
+
|
[96]
|
yes
|
yes
|
|
PEDFd
|
+
|
[97]
|
no
|
yes
|
|
VEGF
|
-
|
[98]
|
yes
|
yes
|
|
Other
|
MDM2
|
+
|
[83]
|
yes
|
yes
|
|
GPX2
|
+
|
[99]
|
no
|
?
|
|
SMARCD3
|
+
|
[29]
|
no
|
?
|
aGenes also involved in apoptosis.
bmetastasis.
cdevelopment.
dneuronal differentiation.
ΔNp63 activity
All ΔN isoforms are lacking of the N-terminal transactivation
domain ( (figure
1A) ), but they possess the entire DNA binding domain. They
may act as dominant negative inhibitors of the full-length versions
of the proteins, thus counteracting their growth suppressive
effects [15]. ΔNp63 isoforms exert this activity either by
competitive binding on the RE of target genes, such as IGF-BP3
[31], or by direct interaction with the TA forms, leading to
inactive oligomers. ΔNp63α appears to be the more potent inhibitor,
probably because of the presence of the SAM and post-SAM domains
able either to recruit some proteins, or to fold up again and to
inactivate the TA domain [32]. The ability to interfere with the
tumour suppressor activity of p53 confers to ΔNp63 isoforms an
oncogenic potential. ΔNp63α exhibits an intrinsic oncogenic
property too, since its ability to interact with APC complex can
lead to the nuclear accumulation of the pro-proliferative β-catenin
protein [33]. Moreover, ΔNp63α is able to enhance the expression of
HSP70, VEGF and ADA genes, via its interaction with some
transcription factors (table 2( Table 2
)).
At the opposite, ΔNp63α, as well as the less studied ΔNp63β and
γ isoforms, have also been shown to induce growth suppression by
exerting an effect towards some p53-target genes [34].
Finally, there is growing evidence that ΔNp63 isoforms may act
themselves as transcriptional factors, in spite of the absence of
the TA domain. Indeed, a transactivation domain encompassing the
amino acids specific to ΔN isoforms and the adjacent proline-rich
domain has been described [34, 35].
Overall, these evidences point to the fact that ΔNp63 may act as
both negative and positive transcriptional regulators, depending on
cell type and differentiation status [36], and on the specific
isoforms [34]. The discrepancies reported above bring out a complex
regulation, probably via some protein interactions, and seem far
from being understood.
Table 2 ΔNp63α-target genes
|
Biological process
|
ΔNp63α-target gene
|
Effect
|
Reference
|
Gene also regulated by
|
|
p53
|
p73
|
|
Cell cycle control
|
p57KIP2
|
+
|
[84]
|
yes
|
yes
|
|
Cell proliferation
|
ADAa
|
+
|
[85]
|
no
|
yes
|
|
Epithelial differentiation
|
S100A2
|
-
|
[100]
|
no
|
yes
|
|
Apoptosis
|
IGF-IR
|
-
|
[94]
|
yes
|
yes
|
|
IGF-BP3
|
-
|
[31]
|
yes
|
yes
|
|
Tumour progression
|
HSP70
|
+
|
[95]
|
yes
|
?
|
|
VEGF
|
+
|
[98]
|
yes
|
yes
|
|
Other
|
GPX2
|
+
|
[99]
|
no
|
?
|
aGene also involved in development.
Regulation of p63 stability and activity
ΔNp63 isoforms are more stable than TA isoforms, suggesting that
p63 protein half-life depends on the N-terminal end. Indeed,
deletions in the TA domain lead to the insensitivity of TAp63
proteins towards the 26S proteasome-mediated degradation [37, 38].
The FWL motif, essential for the mdm2-mediated degradation of p53,
also appears critical for the degradation of TAp63 forms, but in a
mdm2-independent manner [39-42]. Since both DNA binding capacity
and transcriptional activity are required for TAp63 degradation, it
has been suggested that TAp63 isoforms could be able to induce the
expression of protein(s) responsible for their own degradation
(“unknown protein(s)” in ( figure 2 )) [43]. Finally,
the C-terminal end also appears playing a role in the stability of
p63 isoforms, since TAp63α exhibits a longer half-life than TAp63γ
[42]. This stability may be explained by the post-SAM domain in the
α forms, which could protect them from the degradation by binding
to the FWL motif [32].
ΔNp63 can also be degraded by a proteasome-dependent pathway.
Upon cisplatin exposure, this degradation involves stratifin
(14-3-3σ) for nuclear export, and RACK1 as E3 ubiquitin ligase
[44].
All proteins involved in p63 regulation are still far from being
known, but some protein partners of TAp63 have been identified (
(figure 2) ).
Interaction with ASPP1 and 2 [45], PML [46] and Sp1 and Sp3 [47]
proteins stimulates transactivation function of p63, whereas
binding of SSRP1 or p300 proteins leads to an increase of both
transcriptional activity and stability of TAp63 isoforms [48, 49].
Thus ASPP, p300, PML and Sp proteins appear as some common
co-activators of all p53 family members. This is not the case for
p14ARF, which activates and stabilizes p53, but inhibits
both TA and ΔNp63 [50].
Only few post-translational modifications have been described so
far ( (figure 2)
). Some phosphorylations on Ser/Thr residues have been reported.
Upon genotoxic treatment, they result in the stabilisation of
exogenous TAp63α and γ isoforms [37] and, at the opposite, in the
accelerated degradation of ΔNp63α [51]. Also, the SUMOylation of
the p63α isoforms leads to their proteasome-dependent degradation
[52].
Evidence for a role of p63 in stress response
The high homology between p63 and p53 has led to the hypothesis
that p63 could also be involved in the cellular response to stress.
Indeed, TAp63 are required for p53-dependent apoptosis in
fibroblasts upon doxorubicin treatment, probably by modulating the
activity of p53 [12]( (figure 3A) ). Despite some
differences in model and stress signal, this cooperation appears
cell type-dependent, since it has also been found in the developing
central nervous system [12], but not in thymocytes or T cells [53].
If there is clear evidence that TAp73 is involved in
p53-independent response to cisplatin [10], γ-ray [11] and other
stresses [54], only few data are available for TAp63. Exogenous
TAp63α and γ may be stabilized, and then induce differentiation or
cell cycle arrest, under UV-C, actinomycin D, etoposide or
bleomycin treatment in erytholeukemic cells ( (figure 3A) )[37, 55].
Nevertheless, concerning the UV-C-induced increase of TAp63, some
discrepancies remain. They could be explained by the study of
either endogenous or exogenous p63 and underline that results need
to be checked in a more physiological context [56].
Thus, whereas p63 was previously linked almost exclusively to
development and differentiation, several data clearly indicate that
TA forms can also be involved upon treatment with some DNA damaging
agents. In addition, we have recently demonstrated that endogenous
p63 is involved in the response to doxorubicin and etoposide in
hepatocyte [14], a strong chemoresistant cell type [57] where p53
does not appear activated by stress in the same manner than
elsewhere [58]. Although previous studies had showed p63
modulations of the protein only, we observed that, in
hepatocellular carcinoma cell (HCC) lines, these genotoxic
treatments lead to an increase in both the stabilisation, due to
post-translational modifications, and the expression of TAp63 [14,
Petitjean et al., in preparation]. Moreover, in contrast to the
former idea that p63 was involved in cell cycle arrest only,
introduction of TAp63α in HCC cell lines can lead to apoptosis, but
with a delayed kinetic compared to p53 [13]. Exogenous TAp63γ is
also able to induce apoptosis in colon cancer cell lines treated by
doxorubicin. Interestingly, some of these cell lines are resistant
to p53-dependent apoptosis [59]. Finally, TAp63 probably has a role
after oxidative stress too, since it appears able to modulate the
expression of FDXR [60] and REDD1 [61] genes, the products of which
sensitizing cells to ROS (reactive oxygen species).
Thus, in response to stress, TAp63 is able to induce cell
differentiation, cell cycle arrest and also apoptosis. Furthermore,
this role is less tissue-specific than initially suggested from the
first studies on the epidermis after UV treatment. Indeed, in
primary keratinocytes, a rapid decrease in ΔNp63α expression has
been described in response to UV-B, followed by the stabilisation
of p53 protein and the induction of apoptosis [62, 63]. Several
mechanisms have been reported for ΔNp63 inhibition in response to
stress. Among them, the binding of ΔNp63α itself on the
p53-responsive element located in the TP63 promoter P2 [25] and the
phosphorylation of Ser 66/68 and Ser 361 residues [51], that lead
respectively to the inhibition of ΔNp63 expression and to the
proteasome-dependent degradation of ΔNp63 protein. ΔNp63α
phosphorylation on Ser/Thr residues has also been observed
following cisplatin treatment in a head and neck squamous cell
carcinoma cell line (HNSCC), leading to the
stratifin/RACK1-mediated degradation described above [44]. This
indicates that common mechanisms might be involved in ΔNp63
inhibition independently of stress- and cell-types.
All together, these data mean that ΔNp63 acts as a modulator in
stress response and needs to be quickly inhibited upon stress, in
order to allow p53-dependent cell cycle arrest or apoptosis ( (figure 3B) ). We may
hypothesize that this inhibition of ΔNp63 could also allow the
activity of the others members of the p53 family, namely TAp63 and
TAp73 isoforms ( (figure
3B) ).
p63 in carcinogenesis
Recent data showed that DNA-damage response is activated during the
earliest stages of oncogene-induced tumorigenesis, creating a
selection pressure against proteins involved in stress response,
such as p53, for cancer development [64-66]. Therefore, from its
growing role in response to DNA-damaging agents, we may suppose
that deregulation of p63 would be required for tumour formation.
In human cancers, TP63 gene is not frequently mutated [67].
However, an imbalance in the expression of TA and ΔN isoforms for
the benefit of ΔNp63 ones has been reported in squamous cell
carcinoma (SSC) of the nasopharynx [68], skin [69], lung [70],
bladder [71] and oesophagus [72]. This overexpression of ΔNp63 that
results from TP63 gene amplification [70, 72] provides an
additional evidence that ΔNp63 may be a true oncogene. However
direct molecular evidence for a pro-oncogenic role of ΔNp63 is
still lacking and it cannot be ruled out that the amplicon may
contain other genes of interest.
Loss of TAp63 expression has been observed in bladder SSC [71]
and non melanoma skin cancer [69], showing that alteration of TAp63
activity may be observed in several types of tumour. Moreover,
TAp63 activity may be inhibited by some p53 mutants in vitro
[73-75].
Currently, TP63 is emerging as a “non-classical” tumour
suppressor gene. This notion has been demonstrated by the phenotype
of TP63 heterozygous mice [76]. TP63+/- mice develop spontaneous
tumours, in tissues where expression of TP63 is found altered in
human tumours. TP63+/-; TP73+/- double heterozygous mice even show
a larger tumour spectrum and a more aggressive phenotype. Finally,
the tumour types are distinct from those developed by TP53+/- mice.
These data indicate that p63 (and p73) exert a tumour suppressor
activity by themselves and in other tissues than p53.
Alternatively, they can cooperate with p53, as demonstrated by the
dramatically short survival of TP53+/-; TP63+/- and TP53+/-;
TP73+/- double heterozygous mice ( (figure 4) ). However, a
recent study shows that p63 heterozygous mice are not prone to
develop tumours [77]. These opposite results could be due to the
use of distinct mouse models in the two studies.
Flores et al. also notice that TP63+/- mice show signs of
premature aging, in addition to the development of spontaneous
tumours [76]. This observation can be related to the senescence and
organism aging observed after conditional ablation of p63 in mouse
[78]. Since there is accumulating evidence that stress-induced
senescence is a major process in tumour surveillance, the
implication of p63 in senescence needs to be better clarified. More
generally, the respective roles of TA and ΔN isoforms have to be
characterized ( (figure
5) ).
Clinical perspectives
p63 is already used as a relevant marker for the diagnosis of
problematic cancerous lesions in tumours derived from glandular
epithelia, like prostate [79] and breast [80], because it is
specifically expressed in basal or myoepithelial cells. The
identification of the isoforms expressed should further allow
distinguishing between different subtypes of cancers.
The deregulation of p63 activities in some tumours is due to the
imbalance between the expression of suppressive TA isoforms and
oncogenic ΔN isoforms ( (figure 5) ). ΔNp63
overexpression is observed in numerous squamous cell carcinomas
(lung, skin, and oesophagus), where it could suppress the activity
of all the transactivation-competent p53 family members. Such an
up-regulation was also reported for ΔNp73 in other tumour types
[17]. Therefore, functional cross-talk among p53, p63 and p73
should be systematically investigated in the upcoming studies. This
knowledge would allow better understanding their respective role in
tumourigenesis.
p63 also appears as a critical actor in the cellular stress
response of various types of tissue, like colon or liver. This
suggests that p63 status should influence the response to
chemotherapeutic treatments. In fact, TAp63α appears as a
chemosensitivity factor. It is induced by many DNA-damaging agents
and can lead to apoptosis, even in cells resistant to p53-dependent
apoptosis [13, 59]. Alternatively, ΔNp63α overexpression appears as
a good prognostic factor in cisplatin-treated HNSCC [81]. Cisplatin
leads to a decrease in ΔNp63 intracellular level, resulting in a
p73-dependent apoptosis [82]. Such a response cannot be induced in
tumour cells that do not overexpress ΔNp63 [82].
Despite the first emerging picture of a role mainly in
differentiation and development, p63 now appears as a critical
actor in the cancer world. After being described as an oncogene
(ΔNp63) and a biomarker, it takes a growing place as a predictor of
response to chemotherapeutic agents and thus becomes an interesting
target for anti-cancer therapy.
Acknowledgments
p63 work from the two laboratories is supported by a grant from the
Association pour la recherche sur le cancer.
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