Biochimica et Biophysica Acta 1816 (2011) 57–66

Contents lists available at ScienceDirect

Biochimica et Biophysica Acta

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / b b a c a n

Review

Role of p63 in cancer development

Vincenzo Graziano a,b, Vincenzo De Laurenzi a,b,c,⁎
a
Dipartimento di Scienze Biomediche, Universita“G. d'Annunzio” Chieti-Pescara, Via Colle dell'Ara 1, 66100 Chieti, Italy
b
Fondazione “G. D'Annunzio", Centro Studi sull'Invecchiamento, Ce.S.I., Via Colle dell'Ara 1, 66100 Chieti, Italy
c
BioUniverSA srl, DIFARMA, University of Salerno, Fisciano (SA) 84084, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Since their initial identification p53 homologues p63 and p73 have been expected to play a role in cancer
Received 21 February 2011 development due to their close homology to p53, notoriously one of the most mutated genes in cancer.
Received in revised form 5 April 2011 However soon after their discovery the awareness that these genes were rarely mutated in cancer seemed to
Accepted 8 April 2011
indicate that they did not play a role in its development. However a large number of data collected in the
Available online 15 April 2011
following years indicated that altered expression rather than mutation could be found in different neoplasia
Keywords:
and play a role in its biology. In particular p63 due to its fundamental role in epithelial development seems to
p63 play a role in a number of tumors of epithelial origin. In this review we summarize some of the evidence
Oncogenes linking p63 to carcinogenesis.
Oncosuppressors © 2011 Elsevier B.V. All rights reserved.
Cancerogenesis
Molecular biology

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
2. Altered expression of p63 in cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
2.1. Breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
2.2. Squamous cell carcinomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
2.3. Lung cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
2.4. Other cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
3. Potential mechanism explaining the role of p63 in cancer progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
4. Role of p63 in metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
5. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

1. Introduction
p63 belongs to the family of transcription factors that also includes
p53 and p73. All members of the family have three highly conserved
domains: a transactivation domain (TA), a DNA binding domain
(DBD) and an oligomerization domain (OD), p63 and p73 have an
additional protein interacting domain at their c-terminus known as
sterile alpha motif (SAM) (Fig. 1). Based on the high homology
between the three proteins it has initially been postulated that the
⁎ Corresponding author at: Dipartimento di Scienze Biomediche, Universita“G.
d'Annunzio” Chieti-Pescara, Via Colle dell'Ara 1, 66100 Chieti, Italy. Tel.: + 39 0871
541580; fax: + 39 0871 541598.
E-mail address: delaurenzi@unich.it (V. De Laurenzi).
three genes had similar and redundant functions [1–5]. However
over a decade of work has shown that while the three proteins
share some common functions they also have completely unique
physiological roles. Similarly to p53 both p63 and p73 can induce cell
cycle arrest and apoptosis activating similar pathways. This is a
complex gene family and a number of different proteins are generated
from the three genes. In particular alternative splicing results in a
number of variants that differ in the carboxy terminal part of the
protein while usage of an alternative promoter generates amino-
terminally truncated proteins known as ΔN isoforms (Fig. 1). The ΔN
isoforms initially identified for p73 and p63 and more recently also for
p53 lack the TA domain and therefore can have opposite function to
the full length TA isoforms. Indeed it has been shown that these
isoforms promote cell growth and can protect cells from apoptosis
[1,6].

0304-419X/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbcan.2011.04.002
58 V. Graziano, V. De Laurenzi / Biochimica et Biophysica Acta 1816 (2011) 57–66

Fig. 1. Schematic representation of p53 family genes and proteins. (A) p63, (B) p53, (C) p73. Gene structures (upper panels) show alternative splicing and different promoters (P1
and P2) used. Transcribed regions are in white while untranslated regions are in black. Protein structures (lower panels). Main structural domains are indicated: transactivation
domain (TA); DNA binding domain (DBD); oligomerization domain (OD); sterile alpha motif (SAM). All combinations of alternative N-terminus and C-terminus for all proteins are
supposed to be formed.

Results from genetic studies in mice reveal the different functions of ratio but die early as a consequence of inflammation and recurrent
these proteins. While p53 KO mice are viable and do not show any major infections, moreover they show hippocampal dysgenesis, hydrocepha-
developmental defect, but are tumor prone both p73 and p63 KO mice lus and heterozygous animals when aged develop an Alzheimer like
have developmental phenotypes. Total p73 KO are born at a mendelian phenotype [7,8]. Selective TA KO have a similar but milder neuronal
 V. Graziano, V. De Laurenzi / Biochimica et Biophysica Acta 1816 (2011) 57–66 59

phenotype, but in addition show chromosomal instability and develop
spontaneous tumors [9,10]. p63 KO mice show profound alterations of
skin and other stratified epithelia as well as epithelial appendages
including mammary and salivary glands, teeth and hair follicles. These
animals also show truncated limbs and craniofacial abnormalities as a
consequence of an alteration of the apical ectodermal ridge. Similarly
mutations of p63 in humans are responsible for a number of syndromes
known as ectodermal dysplasias. The interpretation of the role of p63 in
epithelial development based on the KO phenotypes however remains
controversial and two interpretation models have been proposed by the
two groups that have independently generated the mice. One model
proposes that p63 is essential for commitment and differentiation of
epithelial precursors while the other suggests that it is essential for
maintenance of the progenitor population [11,12]. A model that can in
part reconcile these two different views has also been proposed and is
supported by some experimental data. In this last model ΔNp63 would
be essential for the maintenance of the progenitor population in the
basal layer while TAp63 would be required together with ΔN or
subsequently to ΔN to allow complete differentiation [1,13–15].
Similarly studies from the same two groups on the ability of p63+/−
mice to develop spontaneous tumors reach opposite conclusions
indicating p63 as an oncogene or a tumor suppressor [16–18].
The described role of p63 isoforms in development of stratified
epithelia implies that altered levels of these proteins can play a role
also in epithelial cancer development. In this review we summarize
the different findings linking p63 to tumor progression and invasive as
well as metastasizing ability of different tumors.
2. Altered expression of p63 in cancer
2.1. Breast cancer
In normal mammary tissues p63 is normally expressed in the
nucleus of a single layer of basal myoepithelial cells surrounding
glandular cells [19,20]. In addition most reports seem to suggest that the
ΔNp63 isoform is the isoform mostly expressed in normal myoepithelial
cells [20] while TA isoform is expressed in the lining cells but absent in
myoepithelial and basal cells [21]. Despite the fact that mutations of this
gene have not consistently been described in breast tumors a number of
reports show that in some cases tumor cells have altered p63 expression
(Table 1). In general p63 over-expression is found only in a small
percentage of breast carcinomas [19,22] however several studies show
that this usually occurs in less differentiated, more aggressive tumors or
some particular subtypes of breast cancer. Indeed p63 increased
expression has been reported in: triple negative basal-like poorly
differentiated ductal carcinomas not otherwise specified [22–26],
sarcomatoid/metaplastic carcinomas [27], adenoid-cystic carcinomas
[20,26,28], myoepithelial–epithelial carcinomas, malignant adeno-
myoepitheliomas [19,20], and invasive papillary carcinomas [29]. In
accordance with the hypothesis that p63 expression is a marker of

Table 1
p63 expression in cancer.

Tumors site Subtypes P63 % Isoforms Prognosis or progression References

Breast Basal-like carcinoma Increased 22% ΔN Increased expression in bigger tumors. [19,20,22,23,25,26,30,33,34]
Increased with nuclear pleomorphism.
Loss correlates with poorer prognosis
Sarcomatoid/metaplastic carcinoma Increased 50–69% Unknown Unknown [27]
Adenoid-cystic carcinoma Increased 100% ΔN Unknown [20,26,28]
Myoepithelial–epithelial carcinoma Increased Unknown ΔN Unknown [19,20]
Malignant adenomyoepithelioma Increased Unknown Unknown Unknown [19,20]
Invasive papillary carcinoma Increased 33.3% Unknown Unknown [29]
Head and neck Squamous cell carcinoma Increased 81–100% ΔN Correlates with both better or [38,40,42–45,49,55–58]
poorer prognosis
Small cell tumors of sino-nasal tract Increased 20–100% ΔN Unknown [39,50]
Merkel cell carcinoma Increased 53.2% Unknown Correlates with poorer prognosis [51]
Sarcomatoid carcinoma Increased 63% Unknown Unknown [41]
Lung Squamous cell carcinoma Increased 88–100% ΔN Correlates with better prognosis [46,49,64,67–69]
Large cell lung cancer Increased 42–66% Unknown Correlates with better prognosis [46,47,49,66–68]
Adenocarcinomas Increased 11–30% ΔN Correlates with better prognosis [46,47,49,66–68,70]
Cytoplasmic expression correlates with
poorer prognosis
Small cell lung cancer Increased 20% Unknown Correlates with poorer prognosis [68,70]
Correlates with higher grade tumors
Large cell neuroendocrine tumors Increased 50–70% Unknown Correlates with poorer prognosis [68,70]
Correlates with higher grade tumors
Sarcomatoid cancer Increased 50% Unknown Unknown [41]
Esophagus Squamous cell carcinoma Increased 52–98% ΔN No correlation [73–83]
Loss correlates with poorer prognosis.
Barret's esophagus Increased Unknown Unknown [77,78]
Bladder Transitional cell carcinoma Incresead 20–75% ΔN Increase in early stage tumors. [85–93]
Decreased Unknown TA Correlates with poorer prognosis.
Sarcomatoid cancer Unknown Unknown Unknown Unknown [41]
Prostate Adenoid-cystic (basal) carcinoma Increased 60–100% Unknown Unknown [105–107]
Adenocarcinoma Increased 3–10% ΔN Cytoplasmic expression correlates [102,108]
with poorer prognosis
Liver Cholangiocarcinoma Increased 23–100% Unknown Unknown [114,115]
Ovary Benign-borderline Brenner tumors Increased 100% Unknown Unknown [110]
Malignant Brenner tumors Increased 17% Unknown Unknown [110]
Serous tumors Increased 0–13% ΔN Correlates with poorer prognosis [37,112,113]
Endometrial tumors Increased 0–25% Unknown Unknown [37,112]
Metastatic transitional cancer cell Increased Unknown Unknown Unknown [111]
Non-Hodgkin Follicular lymphoma Increased 54–99% TA Correlates with poorer prognosis [121–124]
lymphoma Diffuse large B-cell lymphoma Increased 15–34% TA Correlates with poorer prognosis [121–124]
Correlates with better prognosis
Anaplastic large cell lymphoma Increased 44% Unknown Unknown [120]

% indicates the percentage of tumors showing altered p63 expression.

60 V. Graziano, V. De Laurenzi / Biochimica et Biophysica Acta 1816 (2011) 57–66
undifferentiated basal like breast tumors several studies have shown
that more differentiated breast carcinomas such as: lobular like
carcinoma, intra-ductal carcinoma, low grade ductal carcinoma, tubular
and medullary carcinomas are always p63 negative [19,20,29].
Most of the clinical studies reported however do not distinguish
between the different p63 isoforms expressed. When an attempt to
investigate which isoform is expressed in breast cancer cells has been
done it seems that the isoform that is mostly if not exclusively
expressed is the ΔN isoform [30]. It should be mentioned that
occasionally TAp63 expression has been reported as an example
Nylander and colleagues using selective TA and ΔN antibodies show
that while ΔN expression is restricted to basal like tumors cells, TA is
expressed in most breast cancer cells regardless of the subtype [21].
A role for ΔNp63 in basal like breast cancers is in accordance with the
fact that this isoform is normally expressed in cells of the basal layer and
it has been suggested to play a role in immortalization of basal epithelial
cells in early steps of carcinogenesis [31]. In accordance with this Zucchi
and co-workers show that p63 is necessary for the maintenance of
stemness and regeneration of cancer stem cell spheres derived from a
murine breast cancer cell line [32].
Several studies have attempted to correlate p63 expression with
prognosis (Table 1) but further work is required to obtain a clear picture
of the value of this gene as a prognostic marker. A correlation of p63
expression with increased features of poor prognosis [33] has been
reported, indeed expression increases from grade IIIa to grade IIIb–IV
breast carcinomas [19] and correlates with nuclear pleomorphism, a
known feature of aggressive tumors [34]. Moreover in one study it was
reported that p63 is negative in cancers smaller than 2 cm, but its
expression increases with tumor size [19]. Conversely well differenti-
ated tumors over expressing p63 are associated to a good prognosis [23].
It is possible that expression of p63 in cells of different origin has a
different phenotype or more likely that the isoforms expressed by the
different tumors are different and result in a different outcome. Indeed
one could imagine that while basal like tumors express the oncogenic
ΔN isoforms, more differentiated tumors express the tumor suppressor
TA form. Hopefully future studies investigating differential isoform
expression will clarify this point and allow the use of p63 as a prognostic
marker.
Response to therapeutic drugs in vitro also gives potentially
controversial results, as an example increased ΔNp63 levels have been
reported to increase resistance to doxorubicin [35], but also to
increased response to cis-platin [30]. In vivo clinical studies show that
p63 expression in tumor cells correlates with a higher response rate to
cis-platin based chemotherapy regimens [36]. Finally a retrospective
clinical study shows that well differentiated ER positive cancers
expressing m-RNA of p63 in nuclei are associated to a better response
to endocrine therapy than ER positive cancers that do not express it
[23].
2.2. Squamous cell carcinomas
Altered p63 expression patterns have also been found in tumors
derived from pluristratified epithelia (Table 1). While most of the
work done so far reports a role of this gene in squamous cell
carcinomas of the head and neck [37–45] involvement in squamous
tumors of the esophagous and the lung have also been reported and
will be discussed separately [37,46,47].
p63 is over expressed in 81% to 100% [38,44,45] of head and neck
squamous cell carcinomas (HNSCC) [38–45,48,49] as well as in some
particular types of head and neck cancers such as small cell tumors of
sino-nasal tract like nasopharyngeal carcinomas [39,50], Merkel cell
carcinomas (also found in other localizations) [51] and head and neck
sarcomatoid carcinomas (spindle cell carcinomas) [41]. Again most of
the reports that have looked at the expression of different isoforms
show that the ΔN isoform (particularly the α one) is usually the one
over-expressed in these tumors [42,43,50,52] while the expression of
TA isoforms does not seem to have great importance [42,43,50,52].
Within tumors p63 seems to be expressed in non-keratinizing areas of
squamous cancers (both well and poorly differentiated), while it lacks
in central keratinizing areas of well differentiated squamous cancers
[40].
More recent work supports this hypothesis demonstrating a role for
ΔNp63 in the evolution of pre-cancerous lesions like leukoplakia [44],
lichen planus [52], actinic cheilitis [53], or erythroleukoplakia [54] in
malignancies. Interestingly p63 expression is reduced in oral lichen
planus (OLP), a pre-cancerous condition that often shows spontaneous
regression, suggesting a potential causative role in cancer progression.
ΔNp63 is in fact under expressed in OLP lesions compared to the
adjacent normal mucosa while no changes have been reported for TA
isoform expression. This suggests that under-expression of ΔN isoform
is essential for the apoptotic regression typically observed in these
lesions [52,54]. Nuclei of actinic cheilitis of the lips and lip squamous cell
carcinomas show higher levels of p63 compared with normal lips
epithelium [53]. Furthermore over-expression of ΔNp63 in leukoplakias
is correlated to an increased risk of developing oral cancer, and patients
with oral cancer developed from a ΔNp63 negative pre-cancerous lesion
have a cancer-free-survival-rate longer than those derived from ΔNp63
positive ones [44].
The fact that p63 expression is often altered in these cancers has
suggested that it could be an important prognostic marker, however
the number of studies published so far are controversial on this
matter. Some studies show that ΔNp63 over-expression correlates
with a better prognosis [42,55,56], others show that it correlates with
a worse prognosis [51,57,58]. Indeed, Merkel cell carcinomas strongly
staining for p63 are associated to a more aggressive, Ki67 positive
tumor resulting in a lower overall survival of the patients [51]. TAp63
down-regulation has also been associated with more advanced
clinical stage and a greater tumor diameter [59], again supporting
the idea that an imbalance between the two isoforms in favor of ΔN is
responsible for tumor progression. In addition while some studies
seem to suggest that p63 over-expressing tumors show a better
response to cis-platin treatment [55,60–62] others show that p63
over-expressing tumors are more resistant to radiation therapy
treatment [48,63].
2.3. Lung cancer
p63 is strongly expressed in the nuclei of myoepithelial cells
surrounding bronchial and bronchiolar epithelium [37,41,46,47,64–68],
but not in pulmonary epithelium nor in neuroendocrine cells normally
found in the lung [41,66,68].
p63 is often over-expressed in different lung cancers, including:
squamous cell lung cancers[41,46,49,64,67–69], large cell lung cancer,
adenocarcinomas (where it is also occasionally found in the cytoplasm)
[41,46,47,49,66–68,70], high grade neuroendocrine (NET) lung cancers
[68,70], and sarcomatoid cancers [41]. This is particularly relevant in
squamous cell lung cancers where up to 90% show up-regulation of p63.
On the contrary low-grade small cell lung cancers are constantly
negative [64,68,69] in line with the neuroendocrine origin of these cells.
The importance of p63 in lung cancer development is also outlined
by the finding that p63 expression increases from hyperplasia to
metaplasia, to dysplasia reaching its maximum in severe grade
dysplasias [47,65,68]. While most of these clinical studies have not
distinguished between the different p63 isoforms more recent work
suggests again a predominant role for the ΔN isoform [37,46,47,66].
Similarly to what described above for other types of tumors while p63
is clearly over-expressed in some lung cancer its correlation with
prognosis in terms of overall survival and disease-free-survival is less
clear. While some reports show no correlation between expression and
prognosis [68,71] in others increased expression of p63 in NSCLC
(particularly the squamous form) correlates with good prognosis [46,72].
Conversely, over-expression in NET correlates with bad tumor features in
 V. Graziano, V. De Laurenzi / Biochimica et Biophysica Acta 1816 (2011) 57–66
terms of patient performance status, tumor diameter, differentiation and
Ki-67 expression [68] and prognosis [70]. Interestingly the cytoplasmic
expression described in adenocarcinomas associates with poor prognosis
[66] suggesting that in some cases ectopic expression rather than, or
associated with, altered quantitative expression plays a role in cancer
progression.
2.4. Other cancers
p63 is expressed in the basal layer of esophageal mucosa and plays a
role in its development, it is also strongly expressed in nuclei of
squamous esophageal cancer cells (Table 1), mainly as the ΔN isoform
[73–83]. While p63 shows normal expression in esophageal mucosa
collected from areas distant from the tumor its expression increases in
the basal layer of normal mucosa adjacent to the tumor [74] and is over
expressed through the entire thickness of dysplastic lesions [74,78],
suggesting that this could be an early event in initial stages of
carcinogenesis. The finding that p63 is also weakly up-regulated in
Barret's esophagous supports a similar role in the development of
adenocarcinomas [77,78]. p63 over-expression in esophageal tumors
however does not correlate with prognosis while its absence has been
associated with poorer prognosis [75,76,81,82].
p63 is essential for the development of the ventral part of the urinary
bladder and is usually expressed in basal and supra-basal layers of the
urothelium but not in the outer more differentiated umbrella layer
[41,84–88]. Bladder urothelial carcinoma cells (or sarcomatoid ones)
usually express p63 where it seems to play a role in early steps of
carcinogenesis while its expression decreases with tumor size and
advanced tumor stages [41,85–92]. While ΔN isoform seems to be the
predominantly expressed isoform decreasing in higher grade tumors
[86–88,90,93], more dramatic changes are observed for the TA isoform
that shows a drastic reduction in larger less differentiated tumors,
suggesting again that an imbalance between the TA and ΔN isoforms
rather than the reduction of one particular isoform might play a role in
this type of cancer. Indeed Park and co-workers show that while there is
no correlation between ΔN levels and patient's prognosis TA reduction is
strongly correlated to poor prognosis in terms of cumulative survival
[88]. Interestingly loss of p63 (particularly of ΔNp63) correlates with
tumor invasion and metastasis and consequently with poor prognosis
[85–87,93,94].
Prostate requires p63 expression for its development and it is
expressed like in breast, in myoepithelial cells surrounding normal
acinar glands, therefore p63 is routinely used in diagnostics to
evaluate the presence of normal basal cells thus distinguishing
between benign and malign glands [37,95–103]. Similarly to what
reported for other tissues the main isoform expressed in the basal
layer of the prostate is ΔNp63 [104]. However while the majority of
prostate cancer are p63 negative, p63 is consistently over-expressed
in a subgroup of basal like or poorly differentiated tumors: adenoid-
cystic [105,106], [107] and poorly differentiated adenocarcinomas
[102]. Moreover Dhillon and co-workers claim that some adenocar-
cinomas of the prostate show an aberrant cytoplasmic localization of
p63 that correlates with reduced apoptosis and a poor prognosis
[108]. Another study suggests that the ΔN isoform is the one mostly
expressed in these tumors [109].
In addition to the tumors reported above scattered reports suggest a
role of p63 in other tumors (Table 1) such as: ovary tumors [37,110–113],
liver tumors [114,115], pancreas [116,117], poorly differentiated gastric
cancers [118] grade II and III meningiomas with increased cytoplasmic
expression in less differentiated forms [119], squamous cervical cancers
and non-Hodgkin lymphomas (NHL) [120–124].
In some of these tumors a correlation with prognosis has been
attempted again with apparently conflicting results. As an example
expression of p63 in NHL can correlate with better prognosis [121] as
well as with a poorer prognosis [123].
61
3. Potential mechanism explaining the role of p63 in cancer
progression
The number of evidences reported above clearly shows that
altered p63 expression is linked to tumor progression (Table 1),
however the underlying molecular mechanisms are still in part
elusive. Recent reports suggest an important role of this transcription
factor in the maintenance of the cancer stem phenotype, those are the
fraction of cells within a tumor that are capable of propagating it upon
transplantation into immuno-compromised mice [125]. In cells from
head and neck cancers ΔNp63 controls expression levels of CD44 and
basal layer keratins 6A and 14, known markers of more immature
precursors, while it strongly reduces supra-basal keratins 4 and 19
expression suggesting its role in maintaining a less differentiated
phenotype [126]. In addition ΔNp63 induces expression of Inhibitor of
differentiation 3 (Id-3) that is a transcriptional repressor of E-Caderin
which in turn results in inhibition of differentiation of cancer cells,
again contributing to a stem cell like phenotype [127]. Moreover
Zucchi and co-worker show that p63 is essential for maintaining
cancer cell stemness in a population of breast cancer cells that are
those capable of reforming tumors after transplantation in rats while
the subpopulation that lacks p63 fails to do so [32]. Similarly it has
recently been shown that ΔNp63 is essential for the maintenance of
the basal phenotype of primary breast epithelial cells, Notch
expression would down-regulate p63 allowing differentiation [128].
As the other members of the family p63 affect the cell cycle, in
particular ΔNp63 over-expression is known to result in increased cell
proliferation and altered response to growth arrest signals [129], this
is probably due to inhibition of Cyclin Kinase Inhibitor (CKI) p21 and
p57 [130]. Moreover ΔNp63 exerts a dominant negative effect on the
TA form of p63 and on the other family members: p53 and TAp73,
therefore protecting cells from cell death [42,50,131]. Indeed Leong
and co-workers have shown that in triple negative breast cancers
ΔNp63 blocks TAp73 dependent apoptosis, cis-platin would be able to
kill these cells in part by increasing c-abl-dependent phosphorylation
of TAp73 thus disrupting the interaction between p63 and p73 [30]
and allowing p73-dependent apoptosis to occur. Moreover cis-platin
induces proteosomal-mediated ΔNp63 degradation in head and neck
cancer cells, this degradation is mediated by RACK1 functioning as an
E3 ligase [132]. UFD2a an ubiquitin E4 ligase, that normally prevents
ΔNp63 degradation is also down-regulated upon cis-platin treatment
thus allowing ΔNp63 degradation [62]. In addition to a direct
interaction with the other family members other mechanisms
through which p63 affects them have been proposed. As an example
ΔNp63 increases Heat Shock Proteins 70 (HSP70) and this results in
reduced apoptosis partly due to p53 sequestering [133].
ΔNp63 up-regulation can also contribute to tumorigenesis through
the activation of the β-catenin signaling pathway, through reduction of
its phosphorylation and consequent intra-nuclear accumulation [134].
ΔNp63 regulates the AKT pathway [135] protecting cells from apoptosis,
this is at least in part mediated by up-regulation of Fatty Acid Synthase
(FASN) an enzyme involved in long chain fatty acids metabolism, critical
for cell survival [98].
In addition to the reported roles for the ΔNp63 in the mechanisms of
carcinogenesis recent data show that TAp63 acts as a tumor suppressor.
Indeed selective TAp63 mice KO models show increased number of
primary and metastatic tumors [136,137]. This would be due to the
ability of TAp63 to induce senescence. TAp63 induced senescence is p53
independent but requires p21 and Rb [137]. Moreover TAp63 controls
expression of miRs through transcriptional control of Dicer, and altered
expression of some of these miRs would play a direct role in
tumorigenesis [136]. The role of p63 in senescence however appears
to be tissue specific, as an example in keratinocytes loss of both TA and
ΔNp63 or TAp63 alone leads to increased senescence [138,139].
Another open question is what leads to altered expression of p63
in cancer cells. Many different mechanisms both at the transcriptional
62 V. Graziano, V. De Laurenzi / Biochimica et Biophysica Acta 1816 (2011) 57–66
and post-transcriptional level have been proposed and are all
potentially valid and may contribute to p63 deregulation in different
tumors.
p63 expression can be transcriptionally regulated and a number of
transcription factors are known to regulate the p63 promoters, some
of these are known players in cancer formation. Notch decreases
ΔNp63 expression [128,140] and this seems to play a role in deter-
mining the luminal or basal phenotype in mammary cells [128].
TAp63 promoter contains two different binding sites for NF-kB and its
down-regulation leads to inhibition of TA expression [141]. C/EBP
binds ΔNp63 and activates its transcription [142]. ΔNp63 has also
been shown to be under the control of the PI3K pathway in epithelial
cells. This pathway is often altered in human cancer, thus suggesting
that in some cases altered expression of ΔNp63 could be a conse-
quence of increased PI3K activity [143]. In addition TA and ΔNp63
can regulate their own promoters affecting their own expression
[144,145].
Recently it has been shown that miR-203 represses ΔNp63 playing an
essential role in controlling epidermal stemness and differentiation. This
opens the possibility that altered miR-203 expression can result
in altered p63 expression in cancer cells. Interestingly miR-203 is up-
regulated in squamous cell carcinoma cells in response to UVC [145–147].
Other miRs have been shown to regulate p63 such as miR-302 and miR-
92 in testicular cancer and in myeloid cells respectively [148,149].
Multiple mechanisms leading to increased p63 stability through
reduced ubiquitination have been suggested. WWP-1 an E3 ligase for
ΔN and TA p63 is over-expressed in many forms of prostate and breast
cancer explaining why in the majority of these cancers p63 is usually
low. Down-modulation of this protein in cancer cell lines has opposite
effects, depending on the p63 isoform expressed by the cell. Where its
down regulation results in ΔN increase it sensitizes cells to drug induced
death while where it results in TA increase it shows the opposite effect
[35,150].
An interesting observation is that MDM2, that is known to lead to
ubiquitinian degradation of p53, seems to increase the steady state
levels and transactivation function of p63 as well as p73 [151]. In a
similar way SCF (beta TrCP1) that binds and ubiquitylates p63 results
in its stabilization [152]. Degradation of p63 is also mediated by Itch,
another E3 ligase, this pathway is inhibited by Nedd4-binding partner
1 (N4BP1) again an alteration of this degradative pathway, known
to regulate chemosensitivity, could lead to increased p63 levels [153–
Fig. 2. Model describing p63 expression in epithelial cancers. In normal epithelia p63 is mostly expressed in the nuclei of basal cells. In hyperplasia expression is also found in supra-basal
layers. Expression increases in dysplastic and cancers cells, however EMT is favored if p63 is turned off. Secondary cancers might re-express p63 allowing growth of metastatic cells.
156]. It has also been shown that IKKbeta Kinase promotes ubiquitin-
dependent proteosomal degradation of ΔNp63 sensitizing cells to
chemotherapy [157]. Finally P14-ARF, induces sumoylation with
SUMO-2 and degradation of ΔNp63 in keratinocytes [158].
4. Role of p63 in metastasis
While most of the work reported above seems to suggest that
altered levels of p63 are involved in cancer progression and can
influence tumor growth in situ and local invasion, the role of this gene
on the ability of the tumor to form metastasis seems to be completely
different. Indeed a loss of all p63 isoforms seems to play an essential
role in this phenomenon.
Clinical studies show that in different types of cancer including:
head and neck, lung, esophageal and bladder, expression of p63
correlates to reduced invasiveness and metastasization while its loss
promotes invasion [42,46,55,72,76,82,85–88,93,94,159,160], more-
over it has recently been reported that TAp63 selective KO results in
increased metastasis formation in mice [136]. However in breast
cancer this is more controversial, since some authors suggest that over
expression of p63 is associated to increased ability to form metastasis
[19,22,33] while others report that loss of p63 is associated with
invasion [161].
The role of p63 in metastasis is probably linked to its role in
regulating cell adhesion [162] as well as to its involvement in
epithelial–mesenchymal transition (EMT) that is considered the
initial step required for cells to leave the original site and form
metastasis. In vitro studies suggest that disruption of ΔNp63 leads to
expression of mesenchymal and neuronal markers, several of which
are associated with the metastatic phenotype in vivo [160]. Indeed it
has been shown that snail down-regulates ΔNp63 expression and this
in turn results in a more invasive phenotype [163]. Down regulation of
ΔNp63 would lead to invasion through reduction of Vitamin D
receptor (VDR) and Id3 and increase of the Metallo Proteinase 2
(MMP) [127,159]. Moreover, p63 would induce the expression of
tissue inhibitor of matrix metalloproteinase 1 (TIMP1) reducing the
invasive ability of the cells [22]. In addition Adorno and co-workers
demonstrate that p63 is not lost or mutated in cells that acquire a
metastatic phenotype, but more likely is turned off possibly through
the formation of a ternary complex with Smad and mutant p53
induced by TGFβ-signaling [161,164]. In this model p63 could be
 V. Graziano, V. De Laurenzi / Biochimica et Biophysica Acta 1816 (2011) 57–66
reactivated after cells have left the primary tumor site and favor self-
renewal and cancer stem cells regeneration and growth of metastatic
tumors. In line with this idea p63 has been found over-expressed in
secondary sites of primary p63 positive tumors [56,111,165–167].
5. Concluding remarks
While far from having a clear picture of how p63 altered expression
is involved in cancer progression a pattern starts to appear. Indeed the
majority of data would support the idea that increase of ΔNp63 and or
TAp63 reduction results in a more aggressive less differentiated tumor
cell as well as in increased resistance to treatment and thus correlates
with a worse prognosis. However metastasis formation would require
down-regulation of all p63 isoforms in at least a subpopulation of cells
(Fig. 2). In this respect cancers that are already p63 negative would form
metastasis more frequently and earlier on and therefore have a poorer
outcome. This apparently opposite role can explain why often
prognostic studies are controversial.
References
[1] G. Melino, X. Lu, M. Gasco, T. Crook, R.A. Knight, Functional regulation of p73 and
p63: development and cancer, Trends Biochem. Sci. 28 (12) (2003) 663–670.
[2] V. De Laurenzi, G. Melino, Evolution of functions within the p53/p63/p73 family,
Ann. N.Y. Acad. Sci. 926 (2000) 90–100.
[3] V. De Laurenzi, A. Rossi, A. Terrinoni, D. Barcaroli, M. Levrero, A. Costanzo, et al.,
P63 and p73 transactivate differentiation gene promoters in human keratino-
cytes, Biochem. Biophys. Res. Commun. 273 (1) (2000) 342–346.
[4] M. Levrero, V. De Laurenzi, A. Costanzo, J. Gong, G. Melino, J.Y. Wang, Structure,
function and regulation of p63 and p73, Cell Death Differ. 6 (12) (1999)
1146–1153.
[5] M. Levrero, V. De Laurenzi, A. Costanzo, J. Gong, J.Y. Wang, G. Melino, The p53/
p63/p73 family of transcription factors: overlapping and distinct functions, J. Cell
Sci. 113 (Pt 10) (2000) 1661–1670.
[6] G. Melino, V. De Laurenzi, K.H. Vousden, p73: friend or foe in tumorigenesis, Nat.
Rev. Cancer 2 (8) (2002) 605–615.
[7] M.K. Wetzel, S. Naska, C.L. Laliberte, V.V. Rymar, M. Fujitani, J.A. Biernaskie, et al.,
p73 regulates neurodegeneration and phospho-tau accumulation during aging
and Alzheimer's disease, Neuron 59 (5) (2008) 708–721.
[8] A. Yang, N. Walker, R. Bronson, M. Kaghad, M. Oosterwegel, J. Bonnin, et al., p73-
deficient mice have neurological, pheromonal and inflammatory defects but lack
spontaneous tumours, Nature 404 (6773) (2000) 99–103.
[9] Wilhelm MT, Rufini A, Wetzel MK, Tsuchihara K, Inoue S, Tomasini R, et al.
Isoform-specific p73 knockout mice reveal a novel role for delta Np73 in the DNA
damage response pathway. Genes Dev. 24 (6) (2008) 549–560.
[10] R. Tomasini, K. Tsuchihara, M. Wilhelm, M. Fujitani, A. Rufini, C.C. Cheung, et al.,
TAp73 knockout shows genomic instability with infertility and tumor suppres-
sor functions, Genes Dev. 22 (19) (2008) 2677–2691.
[11] A. Yang, R. Schweitzer, D. Sun, M. Kaghad, N. Walker, R.T. Bronson, et al., p63 is
essential for regenerative proliferation in limb, craniofacial and epithelial
development, Nature 398 (6729) (1999) 714–718.
[12] A.A. Mills, B. Zheng, X.J. Wang, H. Vogel, D.R. Roop, A. Bradley, p63 is a p53
homologue required for limb and epidermal morphogenesis, Nature 398 (6729)
(1999) 708–713.
[13] E. Candi, R. Cipollone, P. Rivetti di Val Cervo, S. Gonfloni, G. Melino, R. Knight, p63
in epithelial development, Cell. Mol. Life Sci. 65 (20) (2008) 3126–3133.
[14] E. Candi, D. Dinsdale, A. Rufini, P. Salomoni, R.A. Knight, M. Mueller, et al., TAp63
and DeltaNp63 in cancer and epidermal development, Cell Cycle 6 (3) (2007)
274–285.
[15] E. Candi, A. Rufini, A. Terrinoni, D. Dinsdale, M. Ranalli, A. Paradisi, et al.,
Differential roles of p63 isoforms in epidermal development: selective genetic
complementation in p63 null mice, Cell Death Differ. 13 (6) (2006) 1037–1047.
[16] E.R. Flores, S. Sengupta, J.B. Miller, J.J. Newman, R. Bronson, D. Crowley, et al.,
Tumor predisposition in mice mutant for p63 and p73: evidence for broader
tumor suppressor functions for the p53 family, Cancer Cell 7 (4) (2005) 363–373.
[17] W.M. Keyes, H. Vogel, M.I. Koster, X. Guo, Y. Qi, K.M. Petherbridge, et al., P63
heterozygous mutant mice are not prone to spontaneous or chemically induced
tumors, Proc. Natl. Acad. Sci. USA 103 (22) (2006) 8435–8440.
[18] M.I. Koster, D. Dai, D.R. Roop, Conflicting roles for p63 in skin development and
carcinogenesis, Cell Cycle 6 (3) (2007) 269–273.
[19] A. Ribeiro-Silva, L.N. Zambelli Ramalho, S. Britto Garcia, S. Zucoloto, The
relationship between p63 and p53 expression in normal and neoplastic breast
tissue, Arch. Pathol. Lab. Med. 127 (3) (2003) 336–340.
[20] M. Barbareschi, L. Pecciarini, M.G. Cangi, E. Macri, A. Rizzo, G. Viale, et al., p63, a
p53 homologue, is a selective nuclear marker of myoepithelial cells of the human
breast, Am. J. Surg. Pathol. 25 (8) (2001) 1054–1060.
[21] K. Nylander, B. Vojtesek, R. Nenutil, B. Lindgren, G. Roos, W. Zhanxiang, et al.,
Differential expression of p63 isoforms in normal tissues and neoplastic cells, J.
Pathol. 198 (4) (2002) 417–427.
63
[22] A. Ribeiro-Silva, H. Becker de Moura, F. Ribeiro do Vale, S. Zucoloto, The differential
regulation of human telomerase reverse transcriptase and vascular endothelial
growth factor may contribute to the clinically more aggressive behavior of p63-
positive breast carcinomas, Int. J. Biol. Markers 20 (4) (2005) 227–234.
[23] L. Hanker, T. Karn, E. Ruckhaeberle, R. Gaetje, C. Solbach, M. Schmidt, et al.,
Clinical relevance of the putative stem cell marker p63 in breast cancer, Breast
Cancer Res. Treat. 122 (3) (2009) 765–775 Epub 2009 Nov 7.
[24] A. Ribeiro-Silva, L.N. Zamzelli Ramalho, S.B. Garcia, S. Zucoloto, Is p63 reliable in
detecting microinvasion in ductal carcinoma in situ of the breast? Pathol. Oncol.
Res. 9 (1) (2003) 20–23.
[25] E.A. Rakha, T.C. Putti, D.M. Abd El-Rehim, C. Paish, A.R. Green, D.G. Powe, et al.,
Morphological and immunophenotypic analysis of breast carcinomas with basal
and myoepithelial differentiation, J. Pathol. 208 (4) (2006) 495–506.
[26] H. Liu, Q. Fan, Z. Zhang, X. Li, H. Yu, F. Meng, Basal-HER2 phenotype shows poorer
survival than basal-like phenotype in hormone receptor-negative invasive
breast cancers, Hum. Pathol. 39 (2) (2008) 167–174.
[27] J.S. Reis-Filho, F.C. Schmitt, p63 expression in sarcomatoid/metaplastic carcino-
mas of the breast, Histopathology 42 (1) (2003) 94–95.
[28] M.G. Mastropasqua, E. Maiorano, G. Pruneri, E. Orvieto, G. Mazzarol, A.R. Vento,
et al., Immunoreactivity for c-kit and p63 as an adjunct in the diagnosis of
adenoid cystic carcinoma of the breast, Mod. Pathol. 18 (10) (2005) 1277–1282.
[29] D. Stefanou, A. Batistatou, A. Nonni, E. Arkoumani, N.J. Agnantis, p63 expression in
benign and malignant breast lesions, Histol. Histopathol. 19 (2) (2004) 465–471.
[30] C.O. Leong, N. Vidnovic, M.P. DeYoung, D. Sgroi, L.W. Ellisen, The p63/p73
network mediates chemosensitivity to cisplatin in a biologically defined subset
of primary breast cancers, J. Clin. Invest. 117 (5) (2007) 1370–1380.
[31] J. DiRenzo, S. Signoretti, N. Nakamura, R. Rivera-Gonzalez, W. Sellers, M. Loda,
et al., Growth factor requirements and basal phenotype of an immortalized
mammary epithelial cell line, Cancer Res. 62 (1) (2002) 89–98.
[32] I. Zucchi, S. Astigiano, G. Bertalot, S. Sanzone, C. Cocola, P. Pelucchi, et al., Distinct
populations of tumor-initiating cells derived from a tumor generated by rat
mammary cancer stem cells, Proc. Natl. Acad. Sci. USA 105 (44) (2008) 16940–16945.
[33] S. Garcia, J.P. Dales, E. Charafe-Jauffret, S. Carpentier-Meunier, L. Andrac-Meyer, J.
Jacquemier, et al., Poor prognosis in breast carcinomas correlates with increased
expression of targetable CD146 and c-Met and with proteomic basal-like
phenotype, Hum. Pathol. 38 (6) (2007) 830–841.
[34] Thike AA, Cheok PY, Jara-Lazaro AR, Tan B, Tan P, Tan PH. Triple-negative breast
cancer: clinicopathological characteristics and relationship with basal-like
breast cancer. Mod Pathol 23 (1) (2010) 123–133.
[35] Y. Li, Z. Zhou, C. Chen, WW domain-containing E3 ubiquitin protein ligase 1
targets p63 transcription factor for ubiquitin-mediated proteasomal degradation
and regulates apoptosis, Cell Death Differ. 15 (12) (2008) 1941–1951.
[36] A. Rocca, G. Viale, R.D. Gelber, L. Bottiglieri, S. Gelber, G. Pruneri, et al., Pathologic
complete remission rate after cisplatin-based primary chemotherapy in breast
cancer: correlation with p63 expression, Cancer Chemother. Pharmacol. 61 (6)
(2008) 965–971.
[37] J.S. Reis-Filho, P.T. Simpson, A. Martins, A. Preto, F. Gartner, F.C. Schmitt,
Distribution of p63, cytokeratins 5/6 and cytokeratin 14 in 51 normal and 400
neoplastic human tissue samples using TARP-4 multi-tumor tissue microarray,
Virchows Arch. 443 (2) (2003) 122–132.
[38] M. Wu, A. Kafanas, L. Gan, D.S. Kohtz, L. Zhang, E. Genden, et al., Feasibility of
immunocytochemical detection of tumor markers (XIAP, phosphohistone H1
and p63) in FNA cellblock samples from head and neck squamous cell carcinoma,
Diagn. Cytopathol. 36 (11) (2008) 797–800.
[39] T.D. Bourne, A.M. Bellizzi, E.B. Stelow, A.H. Loy, P.A. Levine, M.R. Wick, et al., p63
expression in olfactory neuroblastoma and other small cell tumors of the
sinonasal tract, Am. J. Clin. Pathol. 130 (2) (2008) 213–218.
[40] D.E. Burstein, C. Nagi, D.S. Kohtz, L. Lee, B. Wang, Immunodetection of GLUT1,
p63 and phospho-histone H1 in invasive head and neck squamous carcinoma:
correlation of immunohistochemical staining patterns with keratinization,
Histopathology 48 (6) (2006) 717–722.
[41] J.S. Lewis, J.H. Ritter, S. El-Mofty, Alternative epithelial markers in sarcomatoid
carcinomas of the head and neck, lung, and bladder-p63, MOC-31, and TTF-1,
Mod. Pathol. 18 (11) (2005) 1471–1481.
[42] J.W. Rocco, C.O. Leong, N. Kuperwasser, M.P. DeYoung, L.W. Ellisen, p63 mediates
survival in squamous cell carcinoma by suppression of p73-dependent
apoptosis, Cancer Cell 9 (1) (2006) 45–56.
[43] K. Nylander, P.J. Coates, P.A. Hall, Characterization of the expression pattern of
p63 alpha and delta Np63 alpha in benign and malignant oral epithelial lesions,
Int. J. Cancer 87 (3) (2000) 368–372.
[44] P. Saintigny, A.K. El-Naggar, V. Papadimitrakopoulou, H. Ren, Y.H. Fan, L. Feng,
et al., DeltaNp63 overexpression, alone and in combination with other
biomarkers, predicts the development of oral cancer in patients with
leukoplakia, Clin. Cancer Res. 15 (19) (2009) 6284–6291.
[45] A. Weber, U. Bellmann, F. Bootz, C. Wittekind, A. Tannapfel, Expression of p53
and its homologues in primary and recurrent squamous cell carcinomas of the
head and neck, Int. J. Cancer 99 (1) (2002) 22–28.
[46] P.P. Massion, P.M. Taflan, S.M. Jamshedur Rahman, P. Yildiz, Y. Shyr, M.E.
Edgerton, et al., Significance of p63 amplification and overexpression in lung
cancer development and prognosis, Cancer Res. 63 (21) (2003) 7113–7121.
[47] P.P. Massion, P.M. Taflan, S.M. Rahman, P. Yildiz, Y. Shyr, D.P. Carbone, et al., Role
of p63 amplification and overexpression in lung cancer development, Chest 125
(5 Suppl) (2004) 102S.
[48] N. Thurfjell, P.J. Coates, B. Vojtesek, P. Benham-Motlagh, M. Eisold, K. Nylander,
Endogenous p63 acts as a survival factor for tumour cells of SCCHN origin, Int. J.
Mol. Med. 16 (6) (2005) 1065–1070.
64 V. Graziano, V. De Laurenzi / Biochimica et Biophysica Acta 1816 (2011) 57–66
[49] K. Hibi, B. Trink, M. Patturajan, W.H. Westra, O.L. Caballero, D.E. Hill, et al., AIS is
an oncogene amplified in squamous cell carcinoma, Proc. Natl. Acad. Sci. USA 97
(10) (2000) 5462–5467.
[50] T. Crook, J.M. Nicholls, L. Brooks, J. O'Nions, M.J. Allday, High level expression of
deltaN-p63: a mechanism for the inactivation of p53 in undifferentiated
nasopharyngeal carcinoma (NPC)? Oncogene 19 (30) (2000) 3439–3444.
[51] S. Asioli, A. Righi, M. Volante, V. Eusebi, G. Bussolati, p63 expression as a new
prognostic marker in Merkel cell carcinoma, Cancer 110 (3) (2007) 640–647.
[52] J.C. Sniezek, K.E. Matheny, M.D. Westfall, J.A. Pietenpol, Dominant negative p63
isoform expression in head and neck squamous cell carcinoma, Laryngoscope
114 (12) (2004) 2063–2072.
[53] F.C. Xavier, C.M. Takiya, S.R. Reis, L.M. Ramalho, p63 immunoexpression in lip
carcinogenesis, J. Mol. Histol. 40 (2) (2009) 131–137.
[54] M. Ebrahimi, L. Boldrup, Y.B. Wahlin, P.J. Coates, K. Nylander, Decreased
expression of the p63 related proteins beta-catenin, E-cadherin and EGFR in
oral lichen planus, Oral Oncol. 44 (7) (2008) 634–638.
[55] R. Zangen, E. Ratovitski, D. Sidransky, DeltaNp63alpha levels correlate with
clinical tumor response to cisplatin, Cell Cycle 4 (10) (2005) 1313–1315.
[56] L.R. Oliveira, A. Ribeiro-Silva, S. Zucoloto, Prognostic significance of p53 and p63
immunolocalisation in primary and matched lymph node metastasis in oral
squamous cell carcinoma, Acta Histochem. 109 (5) (2007) 388–396.
[57] L. Lo Muzio, A. Santarelli, R. Caltabiano, C. Rubini, T. Pieramici, L. Trevisiol, p63
overexpression associates with poor prognosis in head and neck squamous cell
carcinoma, Hum. Pathol. 36 (2) (2005) 187–194.
[58] M.P. Foschini, R. Cocchi, L. Morandi, G. Marucci, M.G. Pennesi, A. Righi, et al., E-
cadherin loss and Delta Np73L expression in oral squamous cell carcinomas
showing aggressive behavior, Head Neck 30 (11) (2008) 1475–1482.
[59] G. Pruneri, L. Pignataro, M. Manzotti, N. Carboni, D. Ronchetti, A. Neri, et al., p63
in laryngeal squamous cell carcinoma: evidence for a role of TA-p63 down-
regulation in tumorigenesis and lack of prognostic implications of p63
immunoreactivity, Lab. Invest 82 (10) (2002) 1327–1334.
[60] J.W. Rocco, L.W. Ellisen, p63 and p73: life and death in squamous cell carcinoma,
Cell Cycle 5 (9) (2006) 936–940.
[61] N. Thurfjell, P.J. Coates, L. Boldrup, B. Lindgren, B. Backlund, T. Uusitalo, et al.,
Function and importance of p63 in normal oral mucosa and squamous cell
carcinoma of the head and neck, Adv. Otorhinolaryngol 62 (2005) 49–57.
[62] A. Chatterjee, S. Upadhyay, X. Chang, J.K. Nagpal, B. Trink, D. Sidransky, U-box-
type ubiquitin E4 ligase, UFD2a attenuates cisplatin mediated degradation of
DeltaNp63alpha, Cell Cycle 7 (9) (2008) 1231–1237.
[63] L. Boldrup, P.J. Coates, X. Gu, K. Nylander, DeltaNp63 isoforms differentially
regulate gene expression in squamous cell carcinoma: identification of Cox-2 as
a novel p63 target, J. Pathol. 218 (4) (2009) 428–436.
[64] M. Wu, B. Wang, J. Gil, E. Sabo, L. Miller, L. Gan, et al., p63 and TTF-1
immunostaining. A useful marker panel for distinguishing small cell carcinoma
of lung from poorly differentiated squamous cell carcinoma of lung, Am. J. Clin.
Pathol. 119 (5) (2003) 696–702.
[65] M. Wu, L. Orta, J. Gil, G. Li, A. Hu, D.E. Burstein, Immunohistochemical detection
of XIAP and p63 in adenomatous hyperplasia, atypical adenomatous hyperplasia,
bronchioloalveolar carcinoma and well-differentiated adenocarcinoma, Mod.
Pathol. 21 (5) (2008) 553–558.
[66] T. Narahashi, T. Niki, T. Wang, A. Goto, D. Matsubara, N. Funata, et al., Cytoplasmic
localization of p63 is associated with poor patient survival in lung adenocar-
cinoma, Histopathology 49 (4) (2006) 349–357.
[67] B.Y. Wang, J. Gil, D. Kaufman, L. Gan, D.S. Kohtz, D.E. Burstein, P63 in pulmonary
epithelium, pulmonary squamous neoplasms, and other pulmonary tumors,
Hum. Pathol. 33 (9) (2002) 921–926.
[68] G. Pelosi, F. Pasini, C. Olsen Stenholm, U. Pastorino, P. Maisonneuve, A. Sonzogni,
et al., p63 immunoreactivity in lung cancer: yet another player in the
development of squamous cell carcinomas? J. Pathol. 198 (1) (2002) 100–109.
[69] H. Zhang, J. Liu, P.T. Cagle, T.C. Allen, A.C. Laga, D.S. Zander, Distinction of pulmonary
small cell carcinoma from poorly differentiated squamous cell carcinoma: an
immunohistochemical approach, Mod. Pathol. 18 (1) (2005) 111–118.
[70] N.H. Au, A.M. Gown, M. Cheang, D. Huntsman, E. Yorida, W.M. Elliott, et al., P63
expression in lung carcinoma: a tissue microarray study of 408 cases, Appl.
Immunohistochem. Mol. Morphol. 12 (3) (2004) 240–247.
[71] T. Iwata, H. Uramoto, K. Sugio, Y. Fujino, T. Oyama, S. Nakata, et al., A lack of
prognostic significance regarding DeltaNp63 immunoreactivity in lung cancer,
Lung Cancer 50 (1) (2005) 67–73.
[72] N.H. Au, M. Cheang, D.G. Huntsman, E. Yorida, A. Coldman, W.M. Elliott, et al.,
Evaluation of immunohistochemical markers in non-small cell lung cancer by
unsupervised hierarchical clustering analysis: a tissue microarray study of 284
cases and 18 markers, J. Pathol. 204 (1) (2004) 101–109.
[73] Y. Daniely, G. Liao, D. Dixon, R.I. Linnoila, A. Lori, S.H. Randell, et al., Critical role of
p63 in the development of a normal esophageal and tracheobronchial
epithelium, Am. J. Physiol. Cell Physiol. 287 (1) (2004) C171–C181.
[74] H. Hu, S.H. Xia, A.D. Li, X. Xu, Y. Cai, Y.L. Han, et al., Elevated expression of p63 protein in
human esophageal squamous cell carcinomas, Int. J. Cancer 102 (6) (2002) 580–583.
[75] L.Y. Cao, Y. Yin, H. Li, Y. Jiang, H.F. Zhang, Expression and clinical significance of
S100A2 and p63 in esophageal carcinoma, World J. Gastroenterol. 15 (33)
(2009) 4183–4188.
[76] Y. Takahashi, T. Noguchi, S. Takeno, Y. Kimura, M. Okubo, K. Kawahara, Reduced
expression of p63 has prognostic implications for patients with esophageal
squamous cell carcinoma, Oncol. Rep. 15 (2) (2006) 323–328.
[77] H. Geddert, S. Kiel, H.J. Heep, H.E. Gabbert, M. Sarbia, The role of p63 and
deltaNp63 (p40) protein expression and gene amplification in esophageal
carcinogenesis, Hum. Pathol. 34 (9) (2003) 850–856.
[78] P.A. Hall, A.C. Woodman, S.J. Campbell, N.A. Shepherd, Expression of the p53
homologue p63alpha and DeltaNp63alpha in the neoplastic sequence of Barrett's
oesophagus: correlation with morphology and p53 protein, Gut 49 (5) (2001)
618–623.
[79] P. Taniere, G. Martel-Planche, J.C. Saurin, C. Lombard-Bohas, F. Berger, J.Y.
Scoazec, et al., TP53 mutations, amplification of P63 and expression of cell cycle
proteins in squamous cell carcinoma of the oesophagus from a low incidence
area in Western Europe, Br. J. Cancer 85 (5) (2001) 721–726.
[80] J.N. Glickman, A. Yang, A. Shahsafaei, F. McKeon, R.D. Odze, Expression of p53-
related protein p63 in the gastrointestinal tract and in esophageal metaplastic
and neoplastic disorders, Hum. Pathol. 32 (11) (2001) 1157–1165.
[81] T. Hara, H. Kijima, S. Yamamoto, T. Kenmochi, Y. Kise, H. Tanaka, et al., Ubiquitous
p63 expression in human esophageal squamous cell carcinoma, Int. J. Mol. Med.
14 (2) (2004) 169–173.
[82] M. Morita, H. Uramoto, S. Nakata, K. Ono, M. Sugaya, T. Yoshimatsu, et al.,
Expression of deltaNp63 in squamous cell carcinoma of the esophagus,
Anticancer Res. 25 (5) (2005) 3533–3539.
[83] A. Thépot, A. Hautefeuille, M.P. Cros, B. Abedi-Ardekani, A. Pétré, O. Damour, V.
Krutovskikh, P. Hainaut, Intraepithelial p63-dependent expression of distinct
components of cell adhesion complexes in normal esophageal mucosa and
squamous cell carcinoma. Int. J. Cancer 127 (9) (2010) 2051–2062.
[84] W. Cheng, W.B. Jacobs, J.J. Zhang, A. Moro, J.H. Park, M. Kushida, et al., DeltaNp63
plays an anti-apoptotic role in ventral bladder development, Development 133
(23) (2006) 4783–4792.
[85] E. Comperat, P. Camparo, R. Haus, E. Chartier-Kastler, S. Bart, A. Delcourt, et al.,
Immunohistochemical expression of p63, p53 and MIB-1 in urinary bladder
carcinoma. A tissue microarray study of 158 cases, Virchows Arch. 448 (3)
(2006) 319–324.
[86] F. Koga, S. Kawakami, Y. Fujii, K. Saito, Y. Ohtsuka, A. Iwai, et al., Impaired p63
expression associates with poor prognosis and uroplakin III expression in invasive
urothelial carcinoma of the bladder, Clin. Cancer Res. 9 (15) (2003) 5501–5507.
[87] F. Koga, S. Kawakami, J. Kumagai, T. Takizawa, N. Ando, G. Arai, et al., Impaired
Delta Np63 expression associates with reduced beta-catenin and aggressive
phenotypes of urothelial neoplasms, Br. J. Cancer 88 (5) (2003) 740–747.
[88] B.J. Park, S.J. Lee, J.I. Kim, C.H. Lee, S.G. Chang, J.H. Park, et al., Frequent alteration
of p63 expression in human primary bladder carcinomas, Cancer Res. 60 (13)
(2000) 3370–3374.
[89] C. Langner, M. Ratschek, O. Tsybrovskyy, L. Schips, R. Zigeuner, P63 immuno-
reactivity distinguishes upper urinary tract transitional-cell carcinoma and
renal-cell carcinoma even in poorly differentiated tumors, J. Histochem.
Cytochem. 51 (8) (2003) 1097–1099.
[90] Y. He, X. Wu, W. Tang, D. Tian, C. Luo, Z. Yin, et al., Impaired delta NP63
expression is associated with poor tumor development in transitional cell
carcinoma of the bladder, J. Korean Med. Sci. 23 (5) (2008) 825–832.
[91] C.J. Di Como, M.J. Urist, I. Babayan, M. Drobnjak, C.V. Hedvat, J. Teruya-Feldstein,
et al., p63 expression profiles in human normal and tumor tissues, Clin. Cancer
Res. 8 (2) (2002) 494–501.
[92] Buza N, Cohen PJ, Pei H, Parkash V. Inverse p16 and p63 expression in small cell
carcinoma and high-grade urothelial cell carcinoma of the urinary bladder. Int J
Surg Pathol 18 (2) (2010) 94–102.
[93] H. Fukushima, F. Koga, S. Kawakami, Y. Fujii, S. Yoshida, E. Ratovitski, et al., Loss
of DeltaNp63alpha promotes invasion of urothelial carcinomas via N-cadherin/
Src homology and collagen/extracellular signal-regulated kinase pathway,
Cancer Res. 69 (24) (2009) 9263–9270.
[94] R. Zigeuner, O. Tsybrovskyy, M. Ratschek, P. Rehak, K. Lipsky, C. Langner,
Prognostic impact of p63 and p53 expression in upper urinary tract transitional
cell carcinoma, Urology 63 (6) (2004) 1079–1083.
[95] S. Signoretti, D. Waltregny, J. Dilks, B. Isaac, D. Lin, L. Garraway, et al., p63 is a
prostate basal cell marker and is required for prostate development, Am. J.
Pathol. 157 (6) (2000) 1769–1775.
[96] M.H. Weinstein, S. Signoretti, M. Loda, Diagnostic utility of immunohistochem-
ical staining for p63, a sensitive marker of prostatic basal cells, Mod. Pathol. 15
(12) (2002) 1302–1308.
[97] A. Kuzmanov, S. Hayrabedyan, M. Karaivanov, K. Todorova, Basal cell
subpopulation as putative human prostate carcinoma stem cells, Folia
Histochem. Cytobiol. 45 (2) (2007) 75–80.
[98] V. Sabbisetti, A. Di Napoli, A. Seeley, A.M. Amato, E. O'Regan, M. Ghebremichael,
et al., p63 promotes cell survival through fatty acid synthase, PLoS One 4 (6)
(2009) e5877.
[99] Garraway IP, Sun W, Tran CP, Perner S, Zhang B, Goldstein AS, et al. Human
prostate sphere-forming cells represent a subset of basal epithelial cells capable
of glandular regeneration in vivo. Prostate 70 (5) 491–501.
[100] M. Zhou, R. Shah, R. Shen, M.A. Rubin, Basal cell cocktail (34betaE12 + p63)
improves the detection of prostate basal cells, Am. J. Surg. Pathol. 27 (3) (2003)
365–371.
[101] L.D. Davis, W. Zhang, A. Merseburger, D. Young, L. Xu, J.S. Rhim, et al., p63
expression profile in normal and malignant prostate epithelial cells, Anticancer
Res. 22 (6C) (2002) 3819–3825.
[102] J.K. Parsons, W.R. Gage, W.G. Nelson, A.M. De Marzo, p63 protein expression is
rare in prostate adenocarcinoma: implications for cancer diagnosis and
carcinogenesis, Urology 58 (4) (2001) 619–624.
[103] O. Hameed, J. Sublett, P.A. Humphrey, Immunohistochemical stains for p63 and
alpha-methylacyl-CoA racemase, versus a cocktail comprising both, in the
diagnosis of prostatic carcinoma: a comparison of the immunohistochemical
staining of 430 foci in radical prostatectomy and needle biopsy tissues, Am. J.
Surg. Pathol. 29 (5) (2005) 579–587.
 V. Graziano, V. De Laurenzi / Biochimica et Biophysica Acta 1816 (2011) 57–66
[104] C. Grisanzio, S. Signoretti, p63 in prostate biology and pathology, J. Cell. Biochem.
103 (5) (2008) 1354–1368.
[105] K.A. Iczkowski, K.L. Ferguson, D.D. Grier, D. Hossain, S.S. Banerjee, J.E. McNeal,
et al., Adenoid cystic/basal cell carcinoma of the prostate: clinicopathologic
findings in 19 cases, Am. J. Surg. Pathol. 27 (12) (2003) 1523–1529.
[106] T.Z. Ali, J.I. Epstein, Basal cell carcinoma of the prostate: a clinicopathologic study
of 29 cases, Am. J. Surg. Pathol. 31 (5) (2007) 697–705.
[107] M.G. Mastropasqua, G. Pruneri, G. Renne, O. De Cobelli, G. Viale, Basaloid cell
carcinoma of the prostate, Virchows Arch. 443 (6) (2003) 787–791.
[108] P.K. Dhillon, M. Barry, M.J. Stampfer, S. Perner, M. Fiorentino, A. Fornari, et al.,
Aberrant cytoplasmic expression of p63 and prostate cancer mortality, Cancer
Epidemiol. Biomarkers Prev. 18 (2) (2009) 595–600.
[109] J.K. Parsons, E.A. Saria, M. Nakayama, R.L. Vessella, C.L. Sawyers, W.B. Isaacs,
et al., Comprehensive mutational analysis and mRNA isoform quantification of
TP63 in normal and neoplastic human prostate cells, Prostate 69 (5) (2009)
559–569.
[110] X.Y. Liao, W.C. Xue, D.H. Shen, H.Y. Ngan, M.K. Siu, A.N. Cheung, p63 expression in
ovarian tumours: a marker for Brenner tumours but not transitional cell
carcinomas, Histopathology 51 (4) (2007) 477–483.
[111] A. Kalebi, M. Hale, p63 expression in ovarian tumours: immunopositivity in
metastatic transitional cell carcinoma of the ovary, Histopathology 53 (2) (2008)
228.
[112] S.L. Shao, Y. Cai, Q.H. Wang, L.J. Yan, X.Y. Zhao, L.X. Wang, Expression of GLUT-1,
p63 and DNA-Pkcs in serous ovarian tumors and their significance, Zhonghua
Zhong Liu Za Zhi 29 (9) (2007) 697–700.
[113] S. Marchini, M. Marabese, E. Marrazzo, P. Mariani, D. Cattaneo, R. Fossati, et al.,
DeltaNp63 expression is associated with poor survival in ovarian cancer, Ann.
Oncol. 19 (3) (2008) 501–507.
[114] F.S. Ramalho, L.N. Ramalho, L. Della Porta, S. Zucoloto, Comparative immuno-
histochemical expression of p63 in human cholangiocarcinoma and hepatocel-
lular carcinoma, J. Gastroenterol. Hepatol. 21 (8) (2006) 1276–1280.
[115] K. Nomoto, K. Tsuneyama, C. Cheng, H. Takahashi, R. Hori, Y. Murai, et al.,
Intrahepatic cholangiocarcinoma arising in cirrhotic liver frequently expressed
p63-positive basal/stem-cell phenotype, Pathol. Res. Pract. 202 (2) (2006) 71–76.
[116] O. Basturk, F. Khanani, F. Sarkar, E. Levi, J.D. Cheng, N.V. Adsay, DeltaNp63
expression in pancreas and pancreatic neoplasia, Mod. Pathol. 18 (9) (2005)
1193–1198.
[117] G. Marucci, C.M. Betts, L. Liguori, V. Eusebi, Basaloid carcinoma of the pancreas,
Virchows Arch. 446 (3) (2005) 322–324.
[118] A. Tannapfel, S. Schmelzer, M. Benicke, M. Klimpfinger, K. Kohlhaw, J. Mossner,
et al., Expression of the p53 homologues p63 and p73 in multiple simultaneous
gastric cancer, J. Pathol. 195 (2) (2001) 163–170.
[119] E.J. Rushing, C. Olsen, Y.G. Man, Correlation of p63 immunoreactivity with tumor
grade in meningiomas, Int. J. Surg. Pathol. 16 (1) (2008) 38–42.
[120] G. Gualco, L.M. Weiss, C.E. Bacchi, Expression of p63 in anaplastic large cell
lymphoma but not in classical Hodgkin's lymphoma, Hum. Pathol. 39 (10)
(2008) 1505–1510.
[121] A.E. Hallack Neto, S.A. Siqueira, F.L. Dulley, M.A. Ruiz, D.A. Chamone, J. Pereira,
p63 protein expression in high risk diffuse large B-cell lymphoma, J. Clin. Pathol.
62 (1) (2009) 77–79.
[122] X.L. Zuo, Y. Zhou, X. Zhou, X.H. Liu, K.J. Zhang, H.Q. Yang, et al., Expression of
survivin and P63 protein in B cell non-Hodgkin's lymphoma and their effects on
cell apoptosis and proliferation, Zhongguo Shi Yan Xue Ye Xue Za Zhi 15 (1)
(2007) 99–102.
[123] N. Fukushima, T. Satoh, N. Sueoka, A. Sato, M. Ide, T. Hisatomi, et al., Clinico-
pathological characteristics of p63 expression in B-cell lymphoma, Cancer Sci. 97
(10) (2006) 1050–1055.
[124] G. Pruneri, S. Fabris, P. Dell'Orto, M.O. Biasi, S. Valentini, B. Del Curto, et al., The
transactivating isoforms of p63 are overexpressed in high-grade follicular
lymphomas independent of the occurrence of p63 gene amplification, J. Pathol.
206 (3) (2005) 337–345.
[125] L. Vermeulen, M.R. Sprick, K. Kemper, G. Stassi, J.P. Medema, Cancer stem cells—
old concepts, new insights, Cell Death Differ. 15 (6) (2008) 947–958.
[126] L. Boldrup, P.J. Coates, X. Gu, K. Nylander, DeltaNp63 isoforms regulate CD44 and
keratins 4, 6, 14 and 19 in squamous cell carcinoma of head and neck, J. Pathol.
213 (4) (2007) 384–391.
[127] K. Higashikawa, S. Yoneda, K. Tobiume, M. Saitoh, M. Taki, Y. Mitani, et al.,
DeltaNp63alpha-dependent expression of Id-3 distinctively suppresses the
invasiveness of human squamous cell carcinoma, Int. J. Cancer 124 (12)
(2009) 2837–2844.
[128] Yalcin-Ozuysal O, Fiche M, Guitierrez M, Wagner KU, Raffoul W, Brisken C.
Antagonistic roles of Notch and p63 in controlling mammary epithelial cell fates.
Cell Death Differ. 17 (10) (2010) 1600–1612.
[129] K.E. King, W.C. Weinberg, p63: defining roles in morphogenesis, homeostasis,
and neoplasia of the epidermis, Mol. Carcinog. 46 (8) (2007) 716–724.
[130] C.T. Chiang, W.K. Chu, S.E. Chow, J.K. Chen, Overexpression of delta Np63 in a
human nasopharyngeal carcinoma cell line downregulates CKIs and enhances
cell proliferation, J. Cell. Physiol. 219 (1) (2009) 117–122.
[131] Mundt HM, Stremmel W, Melino G, Krammer PH, Schilling T, Muller M.
Dominant negative (DeltaN) p63alpha induces drug resistance in hepatocellular
carcinoma by interference with apoptosis signaling pathways. Biochem Biophys
Res Commun 396 (2) (2010) 335–341.
[132] A. Fomenkov, R. Zangen, Y.P. Huang, M. Osada, Z. Guo, T. Fomenkov, et al., RACK1
and stratifin target DeltaNp63alpha for a proteasome degradation in head and
neck squamous cell carcinoma cells upon DNA damage, Cell Cycle 3 (10) (2004)
1285–1295.
65
[133] G. Wu, M. Osada, Z. Guo, A. Fomenkov, S. Begum, M. Zhao, et al., DeltaNp63alpha
up-regulates the Hsp70 gene in human cancer, Cancer Res. 65 (3) (2005)
758–766.
[134] M. Patturajan, S. Nomoto, M. Sommer, A. Fomenkov, K. Hibi, R. Zangen, et al.,
DeltaNp63 induces beta-catenin nuclear accumulation and signaling, Cancer Cell
1 (4) (2002) 369–379.
[135] E. Ogawa, R. Okuyama, S. Ikawa, H. Nagoshi, T. Egawa, A. Kurihara, et al., p51/p63
inhibits ultraviolet B-induced apoptosis via Akt activation, Oncogene 27 (6)
(2008) 848–856.
[136] Su X, Chakravarti D, Cho MS, Liu L, Gi YJ, Lin YL, et al. TAp63 suppresses
metastasis through coordinate regulation of Dicer and miRNAs. Nature 467
(7318) (2010) 986–990.
[137] X. Guo, W.M. Keyes, C. Papazoglu, J. Zuber, W. Li, S.W. Lowe, et al., TAp63 induces
senescence and suppresses tumorigenesis in vivo, Nat. Cell Biol. 11 (12) (2009)
1451–1457.
[138] W.M. Keyes, Y. Wu, H. Vogel, X. Guo, S.W. Lowe, A.A. Mills, p63 deficiency
activates a program of cellular senescence and leads to accelerated aging, Genes
Dev. 19 (17) (2005) 1986–1999.
[139] X. Su, M. Paris, Y.J. Gi, K.Y. Tsai, M.S. Cho, Y.L. Lin, et al., TAp63 prevents
premature aging by promoting adult stem cell maintenance, Cell Stem Cell 5 (1)
(2009) 64–75.
[140] B.C. Nguyen, K. Lefort, A. Mandinova, D. Antonini, V. Devgan, G. Della Gatta, et al.,
Cross-regulation between Notch and p63 in keratinocyte commitment to
differentiation, Genes Dev. 20 (8) (2006) 1028–1042.
[141] Wu J, Bergholz J, Lu J, Sonenshein GE, Xiao ZX. TAp63 is a transcriptional target of
NF-kappaB. J Cell Biochem 109 (4) (2010) 702–710.
[142] S. Borrelli, B. Testoni, M. Callari, D. Alotto, C. Castagnoli, R.A. Romano, et al.,
Reciprocal regulation of p63 by C/EBP delta in human keratinocytes, BMC Mol.
Biol. 8 (2007) 85.
[143] C.E. Barbieri, C.E. Barton, J.A. Pietenpol, Delta Np63 alpha expression is regulated
by the phosphoinositide 3-kinase pathway, J. Biol. Chem. 278 (51) (2003)
51408–51414.
[144] W.K. Chu, K.C. Lee, S.E. Chow, J.K. Chen, Dual regulation of the DeltaNp63
transcriptional activity by DeltaNp63 in human nasopharyngeal carcinoma cell,
Biochem. Biophys. Res. Commun. 342 (4) (2006) 1356–1360.
[145] N. Li, H. Li, P. Cherukuri, S. Farzan, D.C. Harmes, J. DiRenzo, TA-p63-gamma
regulates expression of DeltaN-p63 in a manner that is sensitive to p53,
Oncogene 25 (16) (2006) 2349–2359.
[146] A.M. Lena, R. Shalom-Feuerstein, P. Rivetti di Val Cervo, D. Aberdam, R.A. Knight,
G. Melino, et al., MiR-203 represses ‘stemness’ by repressing DeltaNp63, Cell
Death Differ. 15 (7) (2008) 1187–1195.
[147] R. Yi, M.N. Poy, M. Stoffel, E. Fuchs, A skin microRNA promotes differentiation by
repressing ‘stemness’, Nature 452 (7184) (2008) 225–229.
[148] A.H. Scheel, U. Beyer, R. Agami, M. Dobbelstein, Immunofluorescence-based
screening identifies germ cell associated microRNA 302 as an antagonist to p63
expression, Cell Cycle 8 (9) (2009) 1426–1432.
[149] I. Manni, S. Artuso, S. Careccia, M.G. Rizzo, R. Baserga, G. Piaggio, et al., The
microRNA miR-92 increases proliferation of myeloid cells and by targeting
p63 modulates the abundance of its isoforms, FASEB J. 23 (11) (2009)
3957–3966.
[150] Peschiaroli A., Scialpi F., Bernassola F., El Sherbini el S., Melino G. The E3 ubiquitin
ligase WWP1 regulates DeltaNp63-dependent transcription through Lys63
linkages. Biochem Biophys Res Commun 402 (2) (2010) 425–430.
[151] V. Calabro, G. Mansueto, T. Parisi, M. Vivo, R.A. Calogero, G. La Mantia, The human
MDM2 oncoprotein increases the transcriptional activity and the protein level of
the p53 homolog p63, J. Biol. Chem. 277 (4) (2002) 2674–2681.
[152] J.R. Gallegos, J. Litersky, H. Lee, Y. Sun, K. Nakayama, H. Lu, SCF TrCP1 activates
and ubiquitylates TAp63gamma, J. Biol. Chem. 283 (1) (2008) 66–75.
[153] M. Rossi, R.I. Aqeilan, M. Neale, E. Candi, P. Salomoni, R.A. Knight, et al., The E3
ubiquitin ligase Itch controls the protein stability of p63, Proc. Natl. Acad. Sci.
USA 103 (34) (2006) 12753–12758.
[154] T.M. Hansen, M. Rossi, J.P. Roperch, K. Ansell, K. Simpson, D. Taylor, et al., Itch
inhibition regulates chemosensitivity in vitro, Biochem. Biophys. Res. Commun.
361 (1) (2007) 33–36.
[155] A. Oberst, M. Malatesta, R.I. Aqeilan, M. Rossi, P. Salomoni, R. Murillas, et al., The
Nedd4-binding partner 1 (N4BP1) protein is an inhibitor of the E3 ligase Itch,
Proc. Natl. Acad. Sci. USA 104 (27) (2007) 11280–11285.
[156] G. Melino, R.A. Knight, G. Cesareni, Degradation of p63 by Itch, Cell Cycle 5 (16)
(2006) 1735–1739.
[157] Chatterjee A, Chang X, Sen T, Ravi R, Bedi A, Sidransky D. Regulation of p53 family
member isoform DeltaNp63alpha by the nuclear factor-kappaB targeting kinase
IkappaB kinase beta. Cancer Res 70 (4) (2010) 1419–1429.
[158] M. Vivo, A. Di Costanzo, P. Fortugno, A. Pollice, V. Calabro, G. La Mantia,
Downregulation of DeltaNp63alpha in keratinocytes by p14ARF-mediated
SUMO-conjugation and degradation, Cell Cycle 8 (21) (2009) 3537–3543.
[159] R. Kommagani, M.K. Leonard, S. Lewis, R.A. Romano, S. Sinha, M.P. Kadakia,
Regulation of VDR by deltaNp63alpha is associated with inhibition of cell
invasion, J. Cell Sci. 122 (Pt 16) (2009) 2828–2835.
[160] C.E. Barbieri, L.J. Tang, K.A. Brown, J.A. Pietenpol, Loss of p63 leads to increased
cell migration and up-regulation of genes involved in invasion and metastasis,
Cancer Res. 66 (15) (2006) 7589–7597.
[161] M. Adorno, M. Cordenonsi, M. Montagner, S. Dupont, C. Wong, B. Hann, et al., A
mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metas-
tasis, Cell 137 (1) (2009) 87–98.
[162] D.K. Carroll, J.S. Brugge, L.D. Attardi, p63, cell adhesion and survival, Cell Cycle 6
(3) (2007) 255–261.
66 V. Graziano, V. De Laurenzi / Biochimica et Biophysica Acta 1816 (2011) 57–66

[163] K. Higashikawa, S. Yoneda, K. Tobiume, M. Taki, H. Shigeishi, N. Kamata, Snail-
induced down-regulation of DeltaNp63alpha acquires invasive phenotype of
human squamous cell carcinoma, Cancer Res. 67 (19) (2007) 9207–9213.
[164] J.G. Clohessy, P.P. Pandolfi, Beta-tting on p63 as a metastatic suppressor, Cell 137
(1) (2009) 28–30.
[165] H. Yanai, N. Takahashi, M. Omori, W. Oda, I. Yamadori, S. Takada, et al.,
Immunohistochemistry of p63 in primary and secondary vulvar Paget's disease,
Pathol. Int. 58 (10) (2008) 648–651.
[166] J.L. Hornick, G.Y. Lauwers, R.D. Odze, Immunohistochemistry can help
distinguish metastatic pancreatic adenocarcinomas from bile duct ade-
nomas and hamartomas of the liver, Am. J. Surg. Pathol. 29 (3) (2005)
381–389.
[167] O. Kaufmann, E. Fietze, J. Mengs, M. Dietel, Value of p63 and cytokeratin 5/6 as
immunohistochemical markers for the differential diagnosis of poorly differen-
tiated and undifferentiated carcinomas, Am. J. Clin. Pathol. 116 (6) (2001)
823–830.