Hindawi Publishing Corporation
Journal of Nucleic Acids
Volume 2012, Article ID 687359, 19 pages
p53 Family:Role of ProteinIsoformsinHuman Cancer
Department of Surgery and Cancer Biology, Vanderbilt University Medical Center, 1255 Light Hall, 2215 Garland Avenue,
Nashville, TN 37232, USA
Correspondence should be addressed to Alexander Zaika, email@example.com
Received 29 April 2011; Accepted 4 July 2011
Academic Editor: Didier Auboeuf
Copyright © 2012 Jinxiong Wei et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
TP53, TP63, and TP73 genes comprise the p53 family. Each gene produces protein isoforms through multiple mechanisms
including extensive alternative mRNA splicing. Accumulating evidence shows that these isoforms play a critical role in the
regulation of many biological processes in normal cells. Their abnormal expression contributes to tumorigenesis and has a
profound effect on tumor response to curative therapy. This paper is an overview of isoform diversity in the p53 family and
its role in cancer.
Alternative splicing allows a single gene to express multiple
protein variants. It is estimated that 92–95% of human mul-
tiexon genes undergo alternative splicing [1, 2]. Abnormal
alterations of splicing may interfere with normal cellular
homeostasis and lead to cancer development [3–5].
The p53 protein family is comprised of three tran-
scription factors: p53, p63, and p73. Phylogenetic analysis
revealed that this family originated from a p63/73-like ances-
tral gene early in metazoan evolution [6, 7]. Maintenance
of genetic stability of germ cells seems to be its ancestral
function . The p53 family regulates many vital biological
processes, including cell differentiation, proliferation, and
cell death/apoptosis [9, 10]. Dysregulation of the p53 family
plays a critical role in tumorigenesis and significantly affects
tumor response to therapy. This review summarizes current
data on the regulation of p53, p63, and p73 isoforms and
their roles in cancer.
p53, p63, and p73 genes are located on chromosomes
17p13.1, 3q27-29, and 1p36.2-3, respectively. These genes
encode proteins with similar domain structures and signif-
icant amino acid sequence homology in the transactivation,
DNA-binding and oligomerization domains (Figure 1). The
highest amino acid identity is in the DNA-binding domain
(∼60%). Evolutionally, this domain is the most conserved,
in an array of functions attributed to the p53 family. Less
The founding member of the p53 family, the p53 protein,
had been discovered more than three decades ago [12, 13].
For a long time, it had been assumed that p53 is expressed
as a single polypeptide. However, when it had been found
that the p63 and p73 genes encoded a large variety of diverse
transcripts, the p53 gene transcription was revisited. Now we
know that p53 forms multiple variants.
Transcriptions of p53, p63, and p73 genes are regulated
by similar mechanisms. It is controlled by two promoters:
P1 and P2, where P2 is an alternative intragenic promoter
(Figure 1). One study in silico provided evidence for the
existence of a third putative promoter in the first intron
of human TP73 gene . Therefore, it would not be
surprising if additional gene promoters will be found in the
to the promoters’ products. The produced transcripts and
proteins can be generally categorized into two main groups,
termed TA and ΔN [15, 16]. TA variants contain the N-
terminal transactivation domain while ΔN isoforms lack
the entire (or part of) domain. It was initially thought
that ΔN isoforms are only generated by the P2 promoter
whereas the P1 promoter regulates TA isoforms. Further
analysis of alternative mRNA splicing revealed that some
2Journal of Nucleic Acids
ATG ATG ATG
Figure 1: Architectures of human TP53, TP73, and TP63 genes. (A) TP53, TP73, and TP63 genes encode the transactivation (TAD), DNA-
binding (DBD), and oligomerization (OD) domains. TP73 and TP63 encode additional SAM (Sterile Alpha Motif) domain. Percentage
homology of residues between p53, p63, and p73 is shown . (B) TP53, TP63, and TP73 genes have two promoters (P1 and P2). The P1
promoters produce transactivation-competent full-length proteins (TA) while the P2 promoters produce TAD-deficient proteins (ΔN) with
dominant-negative functions. p53 gene transcription is initiated from two distinct sites (P1 and P1?).
transcriptionally deficient isoforms are products of the P1
promoter. For example, the P1 promoter of the TP73 gene
regulates TAp73 isoforms and isoforms, which lack the
TA domain: ΔEx2p73, ΔEx2/3p73, and ΔN?p73. The latter
isoforms are missing either exon 2 (ΔEx2p73) or both exon
2 and 3 (ΔEx2/3p73) or contain an additional exon 3?
(ΔN?p73) [17, 18]. Other ΔNp73 transcripts are products
of the P2 promoter. Similar to p73, the P1 promoter of
the p53 gene produces transcriptionally active isoforms .
The alternative splicing is responsible for transcriptionally
deficient isoforms of Δ40p53, which missing the first 40
amino acids at the N-terminus [5, 19, 20]. Additional p53
transcriptionally deficient isoforms (Δ133p53 and Δ160p53)
are regulated by the P2 promoter located in intron 4 of the
p53 gene [5, 21].
Additional diversity of p53, p63, and p73 transcripts
is generated by alternative splicing at the 3?end of the
transcripts (Figure 1). These splice variants are traditionally
Journal of Nucleic Acids3
Dominant-negative ΔN proteins
(ΔNp73, ΔNp63, ΔNp53,
and other isoforms)
(p21, Puma, Noxa,
Bax, p53AIP1, ...)
transcriptional and other biological activities of TA isoforms.
named with letters of the Greek alphabet. Initially, three such
splice variants have been described for p63 and p53 (α, β,
γ), and nine for p73 (α, β, γ, δ, ε, θ, ζ, η, and η1) [22–25].
Later, additional p63 splice variants (δ, ε) and p53 (δ, ε, ζ,
ΔE6) were reported [26–28]. However, it should be noted
that a majority of p53, p63, and p73 studies focus on a few
isoforms, primarily α, β, and γ. Little is known about the
functions of other isoforms. The combination of alternative
splicing at the 5?and 3?ends, alternative initiation of
translation and alternative promoter usage can significantly
increase protein diversity. For example, N-terminal variants
(p53, Δ40p53, Δ133p53, and Δ160p53) can be produced in
α, β, and γ “flavors” [20, 21]. Theoretically, the p53 gene can
produce at least 20 isoforms, p63 at least 10, and p73 more
than 40, though not all have been experimentally confirmed.
p53, TAp63, and TAp73 share significant functional
resemblance. They can induce cell cycle arrest, apoptosis, or
cellular senescence. This similarity can be explained, at least
Genome-wide analyses found an overlap of the transcription
profiles of p53, TAp73, and TAp63, though unique targets
were identified as well. Analyses using chromatin immuno-
precipitation, reporter, and gel-shift assays found that TAp73
and TAp63 interact with p53-responsive elements.
The transactivation and apoptotic potential of p53,
TAp73, and TAp63 vary greatly depending on the isoform.
TAp63γ and TAp73β are similar to that of p53α . Other
isoforms are considered less active on the p53 target gene
promoters [9, 23, 30]. Some isoforms are characterized by a
variation in domain structure. TAp73α and TAp63α have an
additional domain at the COOH-terminus that is not found
in p53. This domain, termed SAM or Sterile Alpha Motif, is
responsible for protein-protein interactions and is found in a
diverse range of proteins that are involved in developmental
regulation. It is also implicated in transcriptional repression
. Beta and gamma isoforms of p53 are missing most
of the oligomerization domain that results in decreased
transcriptional activity [5, 32, 33].
ΔN isoforms function as dominant-negative inhibitors
of TA counterparts (Figure 2). Promoter competition and
heterocomplex formation have been suggested to explain
this phenomenon [17, 34, 35]. In the promoter competition
mechanism, the suggestion is that ΔN competes off TA
isoforms from their target gene promoters, thus preventing
efficient transcription. In the heterocomplex formation
mechanism, ΔN isoforms would inhibit TA by forming
ΔN isoforms of p53 and p73 are regulated by a negative
feedback loop mechanism. Analogous mechanism was not
described for p63 despite its significant similarity to p73. In
a nutshell, TA isoforms are able to induce transcription of
ΔN isoforms by activating P2 promoters. The induced ΔN
isoforms, in turn, inhibit TA isoforms. A good example of
these interactions is an induction of Δ133p53 by p53 [5, 36–
38]. Similarly, TAp73 and p53 are important regulators of
transcriptions of ΔNp73 . It appears that the balance
between ΔN and TA isoforms is finely tuned to regulate the
activities of TA isoforms. The net effect of these interactions
in a given context appears to be dependent on the TA/ΔN
expression ratio. Deregulation of this mechanism may lead
to tumor development [40–42]. However, it has become
clear that the role of ΔN isoforms is multifaceted. The
dominant negative concept cannot explain the complexity of
all the interactions attributed toΔN isoforms. Several studies
reported that ΔN isoforms can retain transcription activity
through additional transactivation domains.
3.Role of p53 Isoforms inCancer
Although many aspects of p53 biology have been thoroughly
investigated, the role and regulation of p53 isoforms remain
not well understood.
Recent studies suggested that Δ133p53 isoform may
play an oncogenic role. Mice overexpressing the Δ122p53
isoform (murine homolog of human Δ133p53) show
reduced apoptosis, increased cell proliferation and develop
a wide-spectrum of aggressive tumors including lymphoma,
osteosarcoma, and other malignant and benign tumors .
Another phenotypic characteristic of these mice is elevated
4 Journal of Nucleic Acids
cytokine levels in the blood and widespread inflammation in
many organs. Interestingly, transgenic expression of another
p53 isoform, Δ40p53, does not lead to tumor formation
in mice, but is associated with a short life span, cognitive
between these isoforms [44–46].
Several studies reported an elevated expression of
Δ133p53 in tumors (Table 1). In breast tumors, 24 of 30
cases showed an increased expression of Δ133p53, but low or
undetectable levels in normal breast tissue . An increase
of Δ133p53α mRNA was also found in renal cell carcinoma
. In colon tumors, progression from colon adenoma
to carcinoma is accompanied by an increase of Δ133p53
mRNA. This study suggested that Δ133p53 helps to escape
from the senescence barrier during colon tumor progression
. Interestingly, the Δ133p53 expression level is associated
with the mutation status of p53; colon tumors expressing
wildtype p53 had higher levels of Δ133p53 than p53 mutant
of Δ40p53 was also reported in human melanoma cell
lines and primary melanoma isolates . However, not
all tumors overexpress Δ133p53. Analysis of squamous
changes in the Δ133p53 levels, suggesting that this isoform
may only play a tumor-promoting role in a subset of tissues
Alterationsofp53β andp53γ isoformswerealsoreported
in different types of cancers (Table 1). An increased expres-
sion of p53β was found in renal cell carcinoma and in
most melanoma cell lines. In renal cell carcinoma, p53β
expression was associated with tumor progression .
p53β was also found to correlate with worse recurrence-
free survival in ovarian cancer patients with functionally
active p53 . Decreased p53β and p53γ mRNA levels
were reported in breast cancer . In breast tumors, p53β
is associated with the expression of estrogen receptor but not
with disease outcome . Breast cancer patients expressing
both mutant p53 and p53γ have lower cancer recurrence
and favorable prognosis . Currently, specific functions
of p53β and p53γ remain unclear. A significant hurdle to
the studies of p53 isoforms in tumors is the lack of isoform-
models, and additional tumor studies may help to better
understand the role of p53 isoforms in tumorigenesis.
4. Role of p73 Isoforms inCancer
The role of p73 in tumorigenesis is still a matter of debate.
In contrast to p53, p73 is rarely mutated and frequently
overexpressed in human tumors [23, 52–56]. An initial study
of p73-deficient mice found a number of developmental
defects and no spontaneous tumors . Follow-up studies
have revealed spontaneous tumorigenesis, although the late
onset of tumors and smaller tumor sizes compared to
p53-deficient animals were reported. The basis for these
conflicting results in cancer susceptibility remains obscure
but might be related to the animal genetic background and
housing conditions. Micewithisoform-specific knockouts of
p73 have also been generated; phenotypes of these animals
generally reflect previously reported differences between p73
isoforms. TAp73 null mice are tumor prone while ΔNp73
knockouts have increased sensitivity to DNA-damaging
agents and elevated p53-dependent apoptosis [58, 59].
Several studies have found that N-terminally truncated
isoforms of p73 play an oncogenic role and are linked to
cancer development (Table 1). Targeted transgenic overex-
pression of human ΔEx2/3p73 in the mouse liver resulted
in the development of hepatocellular carcinoma . The
N-terminally truncated isoforms are upregulated in many
human cancers including liver, ovarian, breast, vulvar can-
ΔNp73, which is produced by the P2 promoter, has also
been found to behave as an oncogene. ΔNp73 facilitates
immortalization of primary mouse embryonic fibroblasts
and cooperates with oncogenic Ras in their transforma-
tion. These transformed cells produce tumors following a
subcutaneous injection into nude mice [121, 122]. ΔNp73
also inhibits differentiation of myoblasts and protects them
against apoptosis . Studies by others and us found
that ΔNp73 is upregulated in a number of tumors and is
associated with metastases, chemotherapeutic failure, and
poorer patient prognosis [62, 74, 96, 124–130].
An important question is what causes deregulation of
p73 isoforms in tumors? One of the mechanisms is tumor-
specific alternative mRNA splicing. It has been demonstrated
that the alternative splicing causes incorporation of a new
exon 3’ into TAp73 transcripts resulting in a translational
switch from TAp73 to ?Np73 isoform [18, 61]. An interest-
ing observation was also made in hepatocellular carcinoma
leads to activation of JNK1 kinase, suppression of splicing
factor Slu7, and alternative splicing of p73 transcripts .
Activated Ras has also been shown to decrease TAp73 levels
and increase ΔNp73 expression during cellular transforma-
tion . Abnormal regulation of the P2 promoter has also
(Hypermethylated In Cancer 1) can suppress expression of
ΔNp73 by inhibiting the P2 promoter in normal cells. Loss
of HIC1 in esophagus and gastric cancer cells leads to up-
regulation of ΔNp73 . In a subset of tumors, abnormal
epigenetic changes cause deregulation of p73 isoforms [132–
134]. Hypomethylation of the P2 promoter was found in
more than half of non-small lung cancers .
An increased expression of TAp73 isoforms was also
found in tumors, although its role remains unclear (Table 1).
Several studies suggested that in specific circumstances
TAp73 might play a tumor-promoting role [30, 135]. Inter-
estingly, some tumors tend to increase a variety of p73 splice
isoforms (Figure 3). In the normal colon and breast, p73α
and p73β isoforms are predominant whereas other spliced
variants (γ, δ, φ, and ε) are primarily detected in colon and
breast cancers [15, 23]. This phenomenon was also observed
in acute myeloid leukemia. Moreover, the p73ε isoform was
only expressed in leukemic cells and completely absent in
Journal of Nucleic Acids5
Table 1: Summary of alterations of the p53 family members in human cancers.
Number of casesRef.
(i) p53β was detected in 36% breast tumors and associated with the
expression of estrogen receptor (ER).
(ii) p53γ was detected in 37% breast tumors and associated with
mutations in the p53 gene.
(iii) Patients with mutant p53 and p53γ isoform had a low cancer
recurrence and an overall survival as good as that of patients with wild
127 breast tumors
(i) p53, p53β, and p53γ mRNA, but not transcripts for Δ133p53α,
Δ133p53β mRNA, and Δ133p53γ, were detected in normal breast
(ii) p53β mRNA was detected in 10/30 tumors; Δ133p53α mRNA was
detected in 24/30 tumors; p53γ, Δ133p53β, and Δ133p53γ were
undetected in tumors.
(iii) Some tumors can express mutant p53 but wild type Δ133p53.
(i) ΔTAp73 and TAp73 mRNA were upregulated in tumors.
(ii) Expression of ΔEx2p73 (P = .05) is associated with vascular
invasion; a trend was found between ΔNp73 and vascular invasion
(P = .06).
(iii) Increased expression of ΔEx2p73 and ΔEx2/3p73 were associated
with ER status (P = .06 and P = .07); overexpression of TAp73 was
associated with progesterone receptor expression (P = .06).
30 breast tumors and 8 normal
60 breast cancers
(i) Mutational analysis revealed five silent mutations in 29 hereditary
tumors; no p73 mutations were detected in 48 sporadic cancers.
29 hereditary and 48 sporadic
(i) Thirteen percent of informative cases showed LOH of the p73 gene;
no correlation was found between the p73 LOH and clinical features.
(ii) No changes of p73 transcript levels in breast cancers compared to
normal breast tissues.
(iii) PCR-SSCP analysis did not detect any missense or frameshift
mutations in the p73 gene.
87 primary breast cancer specimens 
(i) Elevated expression of p73 mRNA was found in 29/77 breast tumors;
no correlation of p73 expression with the p53 status.
(ii) New p73 isoforms were identified.
(iii) No coding mutations were found in all coding exons.
(i) p63 protein was strongly expressed in 13/15 metaplastic carcinomas.
(ii) All metaplastic carcinomas with spindle cells and/or squamous
differentiation were positive for p63. One tumor out of 174
nonmetaplastic invasive carcinomas expressed p63.
77 invasive breast cancers
189 invasive breast carcinomas
(i) p63 protein expression was correlated with EBNA-1
immunostaining, suggesting a potential involvement of p63 in
mammary tumorigenesis associated with Epstein-Barr virus infection.
85 breast carcinomas
(i) Survival analysis revealed a better prognosis for ER-positive patients
with p63 mRNA expression; no other correlations were found.
2,158 ER positive breast cancers and
140 normal breast biopsies.
6Journal of Nucleic Acids
Table 1: Continued.
Number of cases Ref.
(i) p73 mRNA expression was increased in 87% (52/60) tumors
compared to normal lung tissues; no correlation with the p53 status was
(ii) No p73 gene amplification was detected.
(iii) p73 expression correlated with cancer histology and patient age.
60 lung cancers
(i) ΔNp73 expression was detected in the cytoplasm of tumor cells in
77/132 patients with lung cancer. No expression was found in the
surrounding normal stromal cells. The expression of ΔNp73 was 52.2%,
50.0%, and 70.2% in stage I, II, and III tumor patients, respectively.
(ii) ΔNp73 expression was a significant independent factor for
predicting poor prognosis.
132 lung cancers
(i) ΔNp73 protein had primarily nuclear expression in 35/40 cases.
(ii) TAp73 protein was found in the cytoplasm in 28/40 cases.
(iii) ΔNp73 expression significantly correlated with p53 expression.
(iv) No methylation of the P1 promoter was found; P2 promoter was
methylated in 17/41 tumors and partially or totally unmethylated in
(i) Hypermethylation of the P1 promoter of the p73 gene was relatively
(ii) Hypomethylation of the P2 promoter was frequently found in
squamous cell carcinomas.
(i) Expression of ΔEx2p73 and ΔEx2/3p73 was increased; expression of
ΔNp73 and ΔN’p73 was decreased.
(ii) Expression of p73 isoforms correlated with clinicopathological
(i) p63 protein expression was detected in 109/118 squamous cell
carcinomas, 15/95 adenocarcinomas, 2/2 adenosquamous carcinomas,
4/6 large cell carcinomas, 9/20 poorly differentiated neuroendocrine
tumors, and 1/37 typical and atypical carcinoids.
(ii) p63 expression was progressively increased from preneoplastic and
preinvasive lesions to invasive squamous cell carcinomas.
(iii) p63 immunoreactivity was correlated with the KI-67 labeling index
and inversely correlated with the tumor grade in squamous cell
221 NSCLCs, 57 stage I–IV
(i) p63 genomic sequence was amplified in 88% of squamous
carcinomas, in 42% of large cell carcinomas, and in 11% of
adenocarcinomas of the lung. Genomic amplification of p63 is an early
event in the development of squamous carcinoma.
(ii) ΔNp63α was found to be the predominant p63 isoform in normal
bronchus and squamous carcinomas but not in normal lung or in
(iii) p63 genomic amplification and protein staining intensity were
associated with better survival.
(i) p63 protein immunopositivity was found in 80% (48/60) NLCLCs.
(ii) Expression of p63 protein was associated with lymph node
metastasis and histological classification.
(iii) Expressions of p63 and p73 proteins were positively correlated.
Journal of Nucleic Acids7
Table 1: Continued.
Protein Cancer typeNumber of casesRef.
(i) Nuclear ΔNp63 staining was found in 77/161 specimens.
(ii) No significant correlation was observed between ΔNp63 expression
and clinicopathological variables.
161 squamous cell carcinomas
(i) Most of the p63 expression detected in nonneoplastic lung tissue was
localized to the nuclei of the bronchiolar basal cells. Nucleic and
cytoplasmic expression of p63 protein was found in 46/92 (50%) and
47/92 (51%) cases. Nuclear localization of p63 was correlated with
nuclear accumulation of p53, but was not associated with patient
(ii) Cytoplasmic expression of p63 was found to be an adverse
prognostic factor in patients with lung adenocarcinoma.
92 lung adenocarcinomas
(i) ΔNp63 isoform was upregulated (P = .02), and TAp63 was slightly
downregulated (P = .01).
(ii) TAp63 expression correlated with patient survival in non-squamous
p73 (i) No tumor-specific mutations were found in the p73 gene.
(ii) p73 was biallelically expressed in both normal prostate and tumor
(iii) p73 mRNA expression was not altered in tumors compared to
27 prostate cancers and 4 prostate
(i) Significant increase of ΔNp73 mRNA was found in 20/33 (60%)
prostate carcinomas and 17/24 (70%) benign prostate hyperplasias.
ΔNp73 mRNA was not detected in the normal prostate. None of the
specimen expressed ΔN?p73.
(ii) ΔNp73 expression was significantly associated with the Gleason
score. No correlation was found between TAp73 expression and clinical
(i) p63 expression was reduced in prostate carcinomas compared to
matched normal tissues.
(ii) One tumor patient had a somatic mutation in exon 11, one prostate
cell line, CWR22Rv1, expressed mutant p63 (G to T substitution in exon
33 prostate carcinomas, 24 benign
prostatic hyperplasia samples, and
5 normal samples
20 tumors, 20 metastases, 28
xenografts, and 7 prostate cancer
(i) Increased expression of cytoplasmic p63 proteins was associated with
increased cancer mortality. Cytoplasmic expression was also associated
with reduced levels of apoptosis and increased cellular proliferation.
298 prostate cancers
(i) Colon adenomas with senescence phenotype expressed elevated
levels of p53β and reduced levels of Δ133p53. Colon carcinoma tissues
were characterized by increased Δ133p53 expression. Colon carcinomas
(stage I and II) had increased levels of p53β mRNA.
(i) p73 protein levels were significantly higher in primary colorectal
(ii) p73 and VEGF expression levels were correlated (P = .016); p73
positive colorectal adenocarcinoma showed significantly greater
(iii) There were no associations between p73 immunostaining and
tumor stage or differentiation.
29 colon carcinomas, 8 adenomas,
and 9 normal colon specimens
56 colon carcinomas with matched
8Journal of Nucleic Acids
Table 1: Continued.
ProteinCancer type Number of casesRef.
(i) TAp73 and ΔTAp73 were significantly co-upregulated in colon
113 colon cancers
(ii) Expression of ΔEx2/3p73 and ΔNp73 isoforms was associated with
tumor stage (P = .03; P = .011).
(iii) ΔNp73 overexpression was significantly associated with vascular
invasion (P = .02).
(iv) High levels of ΔEx2/3p73 were associated with lymph node
metastases (P = .04).
(v) Up-regulation of TAp73 was associated with tumor localization
(P = .004).
(vi) Negative p53 staining correlated with overexpression of ΔEx2p73
and TAp73 (P = .05; P = .05).
(i) p63 protein was primarily expressed in villous adenomas and poorly
(ii) p63 expression was not associated with p53.
30 colon adenomas,
(i) p73 mRNA was increased in 18/45 bladder carcinomas and showed
a strong correlation with tumor stage or grade; no allelic loss was found.
High p73 expression was observed in 4/18 (22.2%), 5/14 (35.7%), and
9/13 (69.2%) of grade I, II, and III tumors, respectively.
(ii) No p73 gene mutations were found by SSCP analysis.
(iii) No relationship between p73 and p53 mutations, expression of p21
and MDM2 was found.
45 primary bladder carcinomas
(i) p73 mRNA was increased in 22/23 bladder cancers.
(ii) No tumor-specific mutations were found in coding exons of
the p73 gene.
(iii) p73 was biallelically expressed in the normal bladder and cancer
23 primary invasive bladder cancers
with matched normal tissues,
7 bladder cancer cell lines
(i) p73 protein was undetectable or low in 104/154 (68%) transitional
cell carcinomas of the bladder, primarily in invasive tumors.
(ii) Expression of p73 was associated with bladder cancer progression.
(i) TAp63 was reduced in 25/47 (53.2%) bladder carcinomas. The
downregulation of TAp63 was associated with tumor stage and grade.
(ii) ΔNp63 was increased in 30/47 (63.8%) tumors.
(iii) No mutations of p63 gene were found.
(iv) No association between p63 expression and the mutational status of
p53 or expression of p21Waf1, MDM2, and 14-3-3σ in carcinomas was
154 bladder transitional cell
47 bladder carcinomas and
12 normal specimens
(i) p63 immunostaining was decreased along tumor progression. Basal
and intermediate cell layers of normal urothelium showed intense
nuclear p63 staining. Lower p63 expression was significantly associated
with TNM stage, lymph-node metastasis, and poor prognosis.
(i) ΔNp63 protein expression was increased in tumors and undetectable
in normal bladder urothelium. ΔNp63 expression was associated with
an aggressive clinical course and poor prognosis. Patients with
ΔNp63-negative tumors had a higher recurrence rate than those with
(ii) p63α expression was decreased in bladder carcinomas.
202 bladder carcinomas and 10
Journal of Nucleic Acids9
Table 1: Continued.
Number of casesRef.
(i) p53β and Δ40p53 mRNAs were expressed in the majority of
melanoma cell lines. These isoforms were absent or expressed at low
levels in fibroblasts and melanocytes. Δ40p53 was found to inhibit
p53-dependent transcription whereas p53β enhances it.
(i) p73 mRNA expressed in the majority of human melanoma cell lines,
melanocytic nevi, primary malignant melanomas, and metastases.
(ii) No mutation was found in the DNA-binding domain of p73 in 9
melanoma cell lines and 5 metastatic tumors.
19 melanoma cell lines
9 cell lines, 17 melanocytic nevi,
17 primary melanomas, and 20
(i) ΔEx2p73 and ΔEx2/3p73 mRNAs were significantly upregulated in
(ii) ΔNp73 was the predominant isoform in benign nevi.
(iii) An increased expression of ΔEx2p73 and ΔEx2/3p73 isoforms
correlated with high levels of TAp73 and E2F1.
8 benign melanocytic nevi,
8 primary melanomas, and
19 melanoma metastases
(i) p73 expression was increased in 37/39 gastric carcinomas and 14/16
(ii) No allelic deletions or mutations in the p73 gene were detected.
(iii) There was no association between p73 expression and mutational
status of p53 or expression of p21/Waf1.
39 gastric carcinomas
(i) p73 expression was found in 33/68 tumors from 24 patients with
multiple simultaneous gastric cancers.
68 gastric carcinomas from 32
(ii) No mutation in the DNA-binding domain of p73 was found.
(iii) No correlations were found between p73 expression and clinical
(i) ΔNp73 mRNA and protein were increased in gastric tumors.
(ii) Up-regulation of ΔNp73 protein was significantly associated with
poor patient survival. The median survival time for patients with
increased ΔNp73 was 20 months whereas that of patients with a
negative/weak expression was 47 months.
(i) p63 expression was found in 25/68 tumors from 24 patients with
multiple simultaneous gastric cancer. p63 expression was significantly
higher in high-grade diffuse tumors. An increased expression of p63 was
observed in intestinal metaplasia and atrophic gastritis. Nonneoplastic
tissues had low levels of p63.
(ii) Expression of TAp63 and ΔNp63 was not associated with the
mutational status of p53, tumor stage, or prognosis.
68 gastric carcinomas from
p73(i) Low expression of p73 mRNA in 8 analyzed tumors.
(ii) No tumor-specific mutation was found.
(iii) LOH for p73 was found in 2/25 (8%) tumors.
48 esophageal tumors (47 ESCCs
and 1 EA)
(i) LOH was found in 9/14 cases.
(ii) No mutations in the p73 gene were detected in tumor samples. A
polymorphism at codon 173 of p73 was identified.
(iii) p73 mRNA was overexpressed in 9/15 tumor samples. Four cases
showed loss of imprinting. Expression of p73 correlated with p53
10Journal of Nucleic Acids
Table 1: Continued.
ProteinCancer type Number of casesRef.
(i) p73 immunoreactivity was reduced with cancer invasion.
(ii) No associations were found between p73 expression and
(iii) Inverse correlation between p73 expression and p53 status was
found. Expression of p21 correlated with the p73 expression.
106 esophageal cancers
(i) Expression of ΔNp73 mRNA and protein was increased in esophageal
(ii) HIC (hypermethylated in tumors 1) protein, but not p53, was found
to regulate ΔNp73.
(iii) Expression of ΔNp73 significantly correlated with the expression of
(i) p63 protein was diffusely expressed in all cases of esophageal
squamous cell dysplasia and carcinoma.
(ii) No expression was found in all cases of esophageal adenocarcinoma
and Barrett’s esophagus.
(iii) ΔNp63 mRNA was a predominant isoform in all benign and
neoplastic squamous tissues.
68 EA and GEJ tumors
20 normal esophageal squamous
tissues, 4 squamous dysplasias,
7 squamous cell carcinomas, 10 BE,
13 BE-associated multilayered
epithelial specimens, 10 esophageal
mucosal gland duct specimens,
12 BE-associated dysplasias, and
7 BE-associated adenocarcinomas
(i) p63 expression was restricted to the basal cell layer in normal
esophageal epithelium. Strong expression of p63 was frequent finding in
squamous precancerous and cancerous lesions. BE-derived lesions
expressed p63 at low levels.
(ii) p63 gene amplification was found to be infrequent in esophageal
malignancies. p63 gene amplification was found in 2/10 squamous cell
carcinomas and in 1/10 adenocarcinomas.
50 esophageal adenocarcinomas, 41
adjacent specialized metaplastic
epithelium, 27 low-grade
intraepithelial neoplasias, and 21
neoplasias, 50 ESCCs, 4 squamous
low-grade intraepithelial neoplasias,
and 18 squamous high-grade
(i) ΔNp63 protein was expressed in 32% and 64% carcinomas with and
without adventitial invasion, and in 37% and 65% with and without
lymph node metastasis, respectively. A better prognosis was observed in
patients with ΔNp63 expression.
(ii) ΔNp63 expression was associated with patient survival. Decreased
expression of p63 was more frequent in advanced carcinomas.
(i) p63 expressed in 171/180 (95%) patients.
(ii) Patients with p63-positive tumors had better overall survival
compared to patients with p63-negative tumors.
(iii) Correlation between p63 and clinicopathological parameters was
not significant. Negative p63 expression tended to correlate with distant
metastases and clinical stage.
180 ESCCs 
(i) Expression of p63 protein was increased in tumors. It was detected in
21/40 (52.5%) ESCCs.
(ii) No associations were observed between expression of p63 protein
and clinicopathological variables.
40 ESCCs and 40 normal
Head and neck cancer
(i) p53β mRNA was detected in 18/20 tumor specimens (T), 13/14
normal tissues adjacent to the tumor (N), and 6/6 normal control
specimens (NS); p53γ was detected in 5/20 (T), 3/14 (N), and 6/6 (NS);
?133p53α expressed in 7/20 (T), 9/14 (N), and 3/14 (NS); Δ133p53β
was detected in 3/20 (T), 2/14 (N); Δ133p53γ expressed in 4/20 (T),
1/14 (N), 2/6 (NS).
21 squamous cell carcinomas,
16 normal specimens adjacent to
tumors, 8 normal specimens
Journal of Nucleic Acids 11
Table 1: Continued.
Protein Cancer type Number of casesRef.
(i) Two missense mutations at codons 469 and 477 and one silent
mutation at codon 349 in the p73 gene were found.
(ii) Increased p73 expression was found in 5/21 (23.8%) patients;
decreased expression was observed in 6/21(28.5%) patients.
67 primary oral and laryngeal
squamous cell carcinomas
(i) p73 mRNA was decreased in 5/17 (30%) tumors. No mutation and
LOH was found in the p73 gene.
(ii) No correlation was found between p73 and p53 protein expression.
50 squamous cell carcinomas
(i) p73 protein expression was detected in 12/68 (18%) normal mucosas
and 32/68 (47%) HNSCC.
(ii) No p73 mutations were found in primary and recurrent carcinomas.
(iii) No correlation was found between protein expression of p73 and
68 squamous cell carcinomas
(i) p73 was significantly elevated in buccal epithelial dysplasia (protein)
and squamous cell carcinomas (protein and mRNA) compared to
normal control tissues.
(ii) p73 expression was associated with cervical lymph node metastasis
for cases of buccal SCC.
(i) Positive immunostaining for p63 was detected in 55/68 (81%)
carcinomas, 40/68 (59%) normal tissues.
(ii) No p63 mutations were detected in primary and recurrent
(iii) No correlation was found between p63 and p53 protein expression.
25 buccal squamous cell
carcinomas, 75 epithelial dysplasias
68 squamous cell carcinomas 
(i) Expression of p63 was associated with tumor differentiation.
p63 expression was increased in poorly differentiated tumors.
(ii) Increased p63 expression was associated with poor patient survival.
No significant correlations were found between p63 expression and sex,
age, tumor size, staging, recurrence, and metastasis. Tumors with diffuse
p63 expression were more aggressive and poorly differentiated.
96 oral squamous cell carcinomas
and 10 normal specimens
(i) ΔNp73 and TAp73α proteins were overexpressed in tumors.
(ii) The overexpression of ΔNp73 was correlated with the resistance to
radiation therapy. An increased expression of TAp73α was detected in
the majority of cervical squamous cell carcinomas sensitive to
(iii) ΔNp73 expression was associated with recurrence of the disease and
an adverse outcome. TAp73α predicted a better survival.
117 cervical squamous cell
carcinomas and 113 normal
(i) Higher TAp73 expression was found in high-grade lesions and
carcinomas (P < .0001).
(ii) No correlation was found between p73 and p63 immunostainings.
(i) Expression of p63 protein was high in 97% squamous cell
carcinomas. p63 is a strong marker for squamous differentiation.
(ii) Transitions from squamous to columnar or undifferentiated tumors
coincided with the loss of p63 expression.
(iii) HPV16 positivity and p63 expression were strong associated.
91 high-grade and 107 low-grade
squamous intraepithelial lesions, 212
ASC-US, 56 squamous cell
carcinomas, and 63 normal specimens
250 cervical carcinomas
(i) ΔNp63 staining was increased with tumor progression. All SCCs,
transitional cell carcinomas, and adenoid basal carcinomas were positive
(ii) ΔNp63 protein was undetected in all adenocarcinomas.
127 uterine cervical tissues with
12Journal of Nucleic Acids
Table 1: Continued.
Protein Cancer type Number of casesRef.
(i) Increased p63 immunostaining was found in high-grade lesions and
(ii) Significant correlation was found between the presence of high-risk
HPV and p63 expression.
(iii) No correlation was found between p63 and p73 immunostainings.
91 high-grade and 107 low-grade
squamous intraepithelial lesions,
212 ASC-US, 56 squamous cell
carcinomas, and 63 normal
(i) All six p53 isoforms were detected in tumor and normal tissues with
the exception of Δ133p53β, which was not detected in normal tissues.
(ii) p53β mRNA was significantly upregulated in tumor samples
(P < .001) and associated with tumor stage.
(i) Monoallelic expression of p73 was found in 11/12 normal tissues;
biallelic expression in 8/12 cancers.
(i) p63 expression was detected in 25/27 (92.6%) urothelial carcinomas.
None of the studied renal cell carcinomas was positive for p63. p63
expression correlated with tumor stage, grade and survival time, but not
with the tumor progression.
41 renal cell carcinomas and normal
tissues adjacent to tumor
28 renal cell carcinomas 
42 renal cell carcinomas and 27
renal pelvis urothelial carcinomas
(i) p73 transcripts were downregulated in adenomas and differentiated
(ii) Expression of TAp73 and ΔNp73 transcripts correlated with
expression of p53, p14ARF, and p16INK4a mRNA in normal tissue.
These correlations were lost in carcinomas.
102 thyroid tissues from 60 patients
(i) ΔNp73 was expressed in 27.3% follicular adenomas, 85.4% follicular
carcinomas, 99.2% papillary carcinomas, and 95.7% anaplastic
carcinomas. Normal follicular cells were negative for ΔNp73 protein. In
papillary carcinoma, ΔNp73 levels were inversely correlated with tumor
size, extrathyroid extensions, and metastases. In anaplastic carcinoma,
ΔNp73 expression was significantly lower than in papillary carcinoma.
(i) TAp63α protein was expressed in 25/27 thyroid cancers 1/7 benign
adenomas, but not in normal thyroid (0/8). TAp63α transcripts, but not
TAp63β, TAp63γ, and ΔNp63, were expressed in tumors. Thyroid cancer
cell lines also expressed p63.
223 thyroid neoplasms
27 thyroid cancers, 11 cell lines 
(i) Expression of p73 protein was detected in 45.6% cancers and was
primarily found in cystic adenocarcinomas.
(ii) p73 expression was inversely correlated with lymph node metastasis,
tumor size, and Ki-67 labeling index.
(iii) No correlation was found between p73 and p53 protein expression.
(i) p73 methylation was found in more than 50% noninvasive and
(i) Overexpression of p63 protein was observed in 68.2% cancers.
(ii) p63 expression was not associated with clinicopathological variables.
(iii) No correlation was found between p63 and p53 protein expression.
28 intraductal papillary mucinous
(i) No ΔNp63 protein expression was found in normal pancreatic ducts
and all pancreatic intraepithelial neoplasias. Among invasive
carcinomas, ΔNp63 expression was detected only in areas of squamous
differentiation and was completely absent in ordinary ductal areas.
ΔNp63 is a reliable marker of squamous differentiation in the pancreas.
It was valuable in distinguishing squamous/transitional metaplasia from
25 nonneoplastic pancreata, 25
pancreatic intraepithelial neoplasia,
and 50 pancreatic ductal
Journal of Nucleic Acids 13
Figure 3: An increased diversity of alternatively spliced species of p73 in colon adenocarcinoma. p73 gene transcription was analyzed in 10
colon tumors and normal colonic mucosa by RT-PCR. Normal specimen 2 represents 14 pooled normal samples. For details, see Vilgelm et
mature myeloid cells . It is currently unclear what role
these changes play in tumorigenesis.
5.Role of p63 Isoforms inCancer
Similar to p73, mutations in the p63 gene are rare in human
cancers [90, 137, 138]. Several studies reported that ΔNp63
has oncogenic properties. Ectopic overexpression of ΔNp63
xenografted into immunocompromised mice, these cells
formed tumors . ΔNp63α inhibits oncogene-induced
cellular senescence and cooperates with Ras to promote
tumor-initiating stem-like proliferation . Analysis of
p63 role in tumorigenesis. p63−/−null mice showed striking
developmental defects demonstrating a critical role of p63 in
epithelial development [141, 142]. p63+/−heterozygous mice
were shown to be susceptible to tumor development .
However, other mouse models were not consistent with this
observation. Conflicting phenotypes of TAp63 and ΔNp63
transgenic mice have also been reported [144, 145].
ΔNp63 is a predominant isoform expressed in most
epithelial cells. Overexpression of ΔNp63 is found in cancers
of nasopharyngeal, head and neck, urinary tract, lung, and
ovarian tumors and correlated with poor outcome [78, 146–
149]. In metastases, ΔNp63 expression was found to be
reduced or lost [91, 101]. Microarray analyses revealed the
up-regulation of genes associated with tumor invasion and
metastasis in p63-deficient cells . It was also reported
that p63 suppresses the TGFβ-dependent cell migration,
invasion, and metastasis . This suggests that ΔNp63
plays a dual role by promoting tumor development but
suppressing metastases [151, 152]. Expression of ΔNp63 was
found to be associated with an increased chemoresistance in
a subset of breast and head and neck tumors [153, 154].
TAp63 isoforms induce cellular senescence and inhibit
cell proliferation [155–157]. TAp63 deficiency increases
proliferation and enhances Ras-mediated oncogenesis .
Decreased TAp63 expression is associated with metastasis
in bladder and breast cancers as well as poor outcome
[42, 90, 158]. TAp63 impedes the metastatic potential of
epithelial tumors by controlling the expression of a crucial
set of metastasis suppressor genes [151, 159].
Clearly, additional studies are needed to understand the
complex regulation of p63 isoforms.
6.Interplayof p53/p63/p73 Isoforms in
Interactions between members of the p53 family and their
isoforms have a profound effect on tumorigenesis and
anticancer drug response. Perhaps, the most studied are
interactions between ΔN and TA isoforms. Inhibition of
TAp73 by ΔNp63 has been shown to negatively affect the
response to platinum-based chemotherapy in head and
neck squamous cell carcinomas and a subset of breast
tumors [153, 154]. In carcinomas of ovary and child-
hood acute lymphoblastic leukemia, increased expression
of dominant-negative p73 isoforms correlates with resis-
tance to conventional chemotherapy [129, 130]. Moreover,
ΔNp73 is primarily expressed in ovarian tumors, which
express wildtype p53 . However, crosstalk between the
p53 family members is not limited to dominant-negative
interactions. Accumulating evidence suggests that the p53
family interacts on multiple levels comprising protein-
protein interactions between multiple p53, p63, and p73
isoforms, shared regulation of target genes as well as TP53
and TP73 gene promoters [160–163]. In addition, mutant
p53 can affect activities of TAp73 and TAp63. It has been
shown that certain tumor-derived p53 mutants (R175H,
R248W, Y220C, R249S, R283H, and D281G) can physically
associate and inhibit activation of TAp73 and/or TAp63
Current analyses suggest that the function of a particular
isoform needs to be investigated in the context of expression
of other isoforms. For example, ΔNp73β inhibits p53-
dependent apoptosis in primary sympathetic neurons ,
but when overexpressed in cancer cells, ΔNp73β induces cell
cycle arrest and apoptosis .
An interesting observation has been made in mouse
embryonic fibroblasts, where the combined loss of p73 and
p63 results in the failure of p53 to induce apoptosis in
response to DNA damage . More recent studies have
reported that the p53 family members can simultaneously
co-occupy the promoters of p53 target genes and regulate
their transcription [15, 170, 171]. Notably, the integral
activity of the entire p53 family, as measured by reporter
14Journal of Nucleic Acids
analysis, is a better predictor of chemotherapeutic drug
response than p53 status alone .
The p53 family plays a pivotal role in the control of many
that all members of the p53 family are expressed as a
diverse variety of isoforms. We only just started to uncover
the mechanisms that regulate this diversity. A number of
studies also provided the first glimpses of their functional
significance. Clearly, isoforms add a new level of functional
regulation to many critical biological processes including cell
death, proliferation, cell cycle control, and tumorigenesis.
Depending on the isoform expressed, the role of a gene
can dramatically change from a tumor suppressor to an
oncogene. It is also clear that p53, p73, and p63 isoforms
tightly interact. A better understanding of this interacting
The authors thank Dr. El-Rifai for the valuable discussions.
This paper was supported by the National Cancer Institute
Grants NIH CA138833 and NIH CA108956.
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