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p53 in health and disease
Karen H. Vousden* and David P. Lane‡
Abstract | As a component of the response to acute stress, p53 has a well established role in
protecting against cancer development. However, it is now becoming clear that p53 can
have a much broader role and can contribute to the development, life expectancy and overall
fitness of an organism. Although the function of p53 as a tumour suppressor ensures that we
can’t live without it, an integrated view of p53 suggests that not all of its functions are
conducive to a long and healthy life.
ChIP analysis
A chromatin immunoprecipitation technique that
identifies proteins that are
bound to promoter sequences
of genes in the context of
endogenous chromatin.
Glycolysis
The metabolic pathway
through which glucose is
metabolized to provide energy.
Autophagy
A process in which parts of the
cytoplasm, including the
organelles it contains, are
engulfed inside a membranous
compartment and targeted to
lysosomes for degradation.
BCL2 family
A family of proteins that share
structural motifs and have an
important role in positively and
negatively regulating
mitochondrial apoptotic
pathways.
*Beatson Institute for Cancer
Research, Garscube Estate,
Switchback Road, Bearsden,
Glasgow G61 1BD, UK.
‡
Institute of Molecular
and Cell Biology,
61 Biopolis Drive,
Singapore 138673.
Correspondence to K.H.V.
e-mail:
[email protected]
doi:10.1038/nrm2147
p53 is an intensively studied protein, its fame stemming
mainly from its clear role as a tumour suppressor in
humans and other mammals1. Loss or mutation of p53
is strongly associated with an increased susceptibility to
cancer, and most functions of p53 have been considered
in the light of how p53 might protect from malignant
progression2. Some p53-null mice can develop normally3,
an observation that has been taken to rule out major functions for p53 in normal physiology. But recent studies are
questioning whether p53 is truly such a single-minded
protein, and other functions of p53 that might be profoundly important during normal life are being uncovered. These include roles for p53 in regulating longevity
and ageing, glycolytic pathways that might determine
endurance and overall fitness, and apoptotic responses
during ischaemic and other types of stress. Evidence for
genetic variations in the activity of the p53 pathway in
humans gives these ideas extra relevance4.
The p53 protein has been extensively studied at both
structural and functional levels (FIGS 1,2). One of the major
mechanisms by which p53 functions is as a transcription
factor that both positively and negatively regulates the
expression of a large and disparate group of responsive
genes5. Although some of these p53-responsive genes
have an important role in mediating cell-cycle arrest,
senescence and apoptosis (the best understood activities
of p53), it is now evident that the ability of p53 to influence
gene expression has wider reaching effects. Numerous
studies, including the recently reported genomewide ChIP analyses6,7, have identified p53-regulated
genes that could have a role in a number of different
— and sometimes unexpected — responses. Although
some of these still need to be fully validated, there is
now clear evidence for a role of p53 in the regulation of
glycolysis8,9 and autophagy10, the repair of genotoxic damage11,
cell survival and regulation of oxidative stress12, invasion
and motility13, cellular senescence14, angiogenesis15,
differentiation16 and bone remodelling17.
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In this review we outline how some of these more
recently described activities of p53 might have a role
not only in regulating cancer progression, but also in
the control of other aspects of health and disease. We
consider some of the signals that activate p53 and
whether the p53 response is always advantageous to our
well-being. We also discuss how some of the apparently
opposing functions of p53 (for example, in driving both
death and survival) might be integrated into an overall
model of p53 activity.
p53: beyond regulating gene expression
The ability of p53 to regulate gene expression is key for
the activation of the responses shown in FIG. 1. However,
transcriptionally independent activities of p53 that
can potentiate the apoptotic response have also been
described18. These functions involve a direct interaction
of p53 with members of the BCL2 family of proteins,
allowing p53 to function as a so-called BCL2-homology
domain-3 (BH3)-only protein (BOX 1). Some discussion
remains about the exact nature of this activity of p53,
with evidence for functions both in the cytosol and
directly at the mitochondria19. However, it seems clear
that the transcriptionally independent apoptotic activity
of p53 complements its ability to activate the expression of
pro-apoptotic BH3-only proteins at the transcriptional
level, as interfering with either of these functions can
severely impair the death response. For example,
mice that lack PUMA — one of the key apoptotic transcriptional targets of p53 — show profound defects in
their apoptotic response following the induction of p53
in many tissues20. On the other hand, a small molecule
that inhibits the interaction of p53 with anti-apoptotic
BH3 proteins can also dramatically reduce the p53dependent apoptotic response without hindering the
transcriptional functions of p53 (REF. 21). Interestingly,
there is a direct link between the transcriptional and
cytoplasmic functions of p53 in that PUMA — the
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Hypoxia
DNA damage
Ribosomal stress
Telomere erosion
Oncogene activation
Nutrient deprivation
p53
Apoptosis
Senescence
Cell-cycle arrest
Genomic stability
Survival
DNA repair
Figure 1 | Activation and functions of p53. p53 has a key role in integrating the
cellular responses (pink boxes) to different types of stress (blue boxes). Activation of p53
can result in a number of cellular responses, and it is possible that different responses are
induced by different stress signals. There is evidence that p53 can play a part in
determining which response is induced through differential activation of target-gene
expression. Although the importance of these responses to tumour suppression is clear,
previously unanticipated contributions of these responses to other aspects of human
health and disease are being uncovered. The role of p53 in tumour suppression,
development and ageing is likely to depend on which cellular response is activated and
on the context in which the activation occurs.
elevated expression of which results from the transcriptional activity of p53 — can dislodge cytoplasmic p53 from
an inhibitory interaction with the anti-apoptotic BH3 proteins, and so activate the transcriptionally independent
apoptotic function of p53 (REF. 22) (BOX 1).
PUMA
(p53-upregulated mediator of
apoptosis). A protein that
belongs to the BCL2 family and
that promotes mitochondrial
outer membrane
permeabilization and
apoptosis.
Ubiquitin ligase
An enzyme that can transfer
ubiquitin onto a protein, which
can target the protein for
degradation by the
proteasome.
MDM2
A ubiquitin ligase that
functions as an important
negative regulator of p53. As
the product of a p53-inducible
gene, MDM2 functions in a
negative-feedback loop with
p53.
Control and release of p53
p53, through its cell-cycle-arrest and apoptotic activities, can have a strong inhibitory effect on cell growth,
making it essential to hold p53 function in check
during normal development. Multiple mechanisms
exist to negatively control p53, including the regulation of protein activity, stability and subcellular localization through the action of numerous other proteins
that work directly or indirectly to restrain p53. These
p53-regulatory proteins include ubiquitin ligases that
have a role in controlling p53 protein stability, enzymes
involved in post-translational modification of p53
(such as kinases and acetylases), transcriptional coactivators that can modulate the transcriptional activity
of p53, and many more (as described in a number of
excellent recent reviews5,23–26). Loss of these regulators,
and subsequent failure to rein in p53 function, can have
disastrous consequences to the survival of the organism. This is nicely illustrated by MDM2, one of the key
ubiquitin ligases responsible for limiting the levels of
p53. Deletion of Mdm2 in mice results in an extremely
early embryonic lethality that is the direct result of a
failure to restrain p53-mediated apoptosis27.
Signals to activate p53 — are they all equal? Release
of the tight control over p53 and activation of p53 is
a well established response to stress. Analysis of the
p53 orthologue in flies and worms shows that, as seen
in mammalian systems, p53 is an integral part of the
response to genotoxic stress28–30. p53 is extremely sensitive to even low levels of DNA damage, a response that
is thought to contribute to tumour suppression by either
allowing for repair or by eliminating cells harbouring
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potentially oncogenic alterations. However, many other
signals can also activate p53, including inappropriate
cell proliferation driven by oncogene activation, telomere erosion, nutrient deprivation and hypoxia 23
(FIG. 1). Importantly, these signals do not all engage p53
through the same pathways, but use different signalling
molecules to stabilize and activate p53. For example,
ARF, a small protein that binds and inhibits MDM2,
has an important role in signalling to p53 in response
to some oncogenes, but is not necessary for the activation of p53 in response to DNA damage31. Similarly, the
ribosomal protein L11 has a role in activating p53 in
response to ribosomal stress without a requirement for
ARF32. So, different signals use different pathways to
activate p53, leading to the interesting question: are all
of these pathways equally important for the inhibition of
tumour development?
Although a response to genotoxic stress certainly
seems to be the most ancient function of p53 in evolutionary terms, a recent study using a mouse model in
which p53 can be switched on and off has indicated
that the response of p53 to DNA damage might not
be responsible for tumour suppression33. The studies
show that p53 becomes important only after the bulk
of the damage has been resolved, and conclude that the
key tumour-suppressive function of p53 is to respond
to oncogene activation that occurs as a consequence of
the original genotoxic stress. Supporting this idea are
studies showing that ARF — which is necessary for
oncogene-induced, but not DNA-damage-induced,
activation of p53 — is responsible for almost all the
tumour-suppressor activity of p53 (REF. 34). These are
startling and provocative suggestions because they
make us reconsider the utility of the p53 response to
DNA damage in regards to tumour suppression as well
as the true role of p53 in DNA repair. Undoubtedly
there will be modifications, complications and caveats
to this story. Other equally compelling studies indicate
that genotoxic stress is the key signal to activate p53
and tumour suppression in pre-cancerous lesions, and
that DNA damage can be induced by the activation of
several oncogenes in an ARF-independent manner35,36.
p53 activation by everyday stresses
Despite the clear importance of the negative regulation
of p53 during normal cell growth, a number of recent
studies have led us to question one of the basic tenets
of the field — that p53 is held entirely inactive until
induced by unusual, sporadic or severe stress, such as
acute genotoxic stress or oncogene activation. It has
become evident that despite the many levels of negative
regulation that are in place to restrain p53, the everyday
rigours of normal mammalian life can more systemically induce low levels of p53 activity. And, recent studies
have revealed a hitherto unappreciated importance of
p53 under conditions of apparently normal growth and
development. Interestingly, induction of p53 through
these mechanisms seems to have a role in responses
beyond cell-cycle arrest and apoptosis, including an
intriguing role of p53 in promoting survival37 as well
as cell death.
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TransProline-rich
activation domain
Sequence-specific
DNA-binding domain
Oligomerization
domain
p53
Phosphorylation
Point mutations in tumours
Phosphorylation
Acetylation
Methylation
Ubiquitylation
Neddylation
Sumoylation
p73
SAM
domain
p63
Figure 2 | Structure of p53 family members. The major functional domains of the p53
protein are shown, including the N-terminal transactivation domains, the central
sequence-specific DNA-binding domain and the C-terminal regulatory domain. p53 is
subject to numerous post-transcriptional modifications, including phosphorylation,
acetylation, methylation and modification with ubiquitin-like proteins, that can affect
the function and stability of p53. Phosphatases, de-acetylases and de-ubiquitylating
enzymes have been identified that can reverse most of these modifications. Most of the
point mutations found in naturally occurring cancers occur in the central DNA-binding
domain, and the position of the hotspots for these mutations are indicated by the orange
lightning bolts. The p53-related proteins p63 and p73 show a similar overall structure,
although some isoforms of these p53 relatives also contain a C-terminal sterile α-motif
(SAM) domain. Multiple isoforms of each of these proteins have now been described16.
Warburg effect
An increase in aerobic
glycolysis that is characteristic
of cancer cells.
Regulation of glucose metabolism. Recent results have
indicated a role for p53 in determining the response
of cells to nutrient stress and in regulating pathways of
glucose usage and energy metabolism (FIG. 3). Metabolic
stress that results in low glucose levels has been shown
to activate p53 through a pathway that involves AMP
kinase (AMPK), and has been proposed to contribute to
the short-term survival of cells suffering, hopefully temporary, starvation38. However, the loss of this response in
tumours that lack functional p53 might also contribute
to the capability of these cells to continue to proliferate
in nutrient-poor conditions, and so provide a proliferative advantage to tumour cells that are attempting to
grow abnormally. Such a starvation-induced activity
of p53 is entirely consistent with the concept of p53 as
a sentinel in the detection and response to potentially
oncogenic stress, but could clearly have a much broader
role in the response to metabolic stress.
More surprisingly, roles for p53 in controlling different metabolic pathways under apparently normal
growth conditions has also been recently described.
For example, p53 has been shown to induce the
expression of the copper transporter SCO2, which is
required for the assembly of cytochrome c oxidase8.
This allows p53 to enhance oxidative phosphorylation. Conversely, the loss of p53 activity in cells results
in a reduction in oxygen consumption. The resultant
defect in respiration would affect tumour cells (which
are all defective in some way for p53 activity) particularly strongly, because the abnormal and deregulated
proliferation that is characteristic of cancer cells makes
them particularly energy demanding. In cancers, a dramatic increase in glycolysis — called the Warburg effect
— might help solve this problem of sustained energy
production. Interestingly, loss of p53 seems to be a root
cause of the metabolic changes that characterize cancer
cells, because restoration of SCO2 expression in p53deficient cancer cell lines can restore mitochondrial
respiration8. Similarly, basal levels of p53 have been
shown to have a role in regulating AIF expression, a
mitochondrial protein that also contributes to efficient
oxidative phosphorylation39.
But what effect does this change in mitochondrial
respiration have on the whole animal? Closer examination of p53-null mice led to the identification of an
interesting, and hitherto undetected, defect in endurance. p53-null mice get exhausted very quickly during
exercise — presumably because they cannot efficiently
generate energy through aerobic respiration8. This might
be one of many cancer-independent phenotypes that
results from the loss of p53 that have been overlooked
owing to our extreme focus on tumour development.
Box 1 | Apoptotic pathways and p53
One of the most dramatic responses to p53 is the induction of apoptosis, a type of programmed cell death. Apoptotic
signals can engage two main pathways (which are also interconnected). These are the extrinsic pathway, which is
induced through the activation of cell-surface receptors, and the intrinsic pathway, which responds to stress signals98.
Although p53 has been implicated in both pathways, it predominantly seems to influence the intrinsic pathway. This
apoptotic pathway leads to a perturbation of mitochondrial membrane potential, and so the release of apoptogenic
factors from the mitochondrial intermembrane space into the cytoplasm. This triggers a cascade of events leading to
caspase activation and cell death99. A family of proteins with structurally conserved domains, known as the BCL2homology (BH) domains, have a central role in the intrinsic apoptotic pathway. Two of these BH-domain proteins, BAX
and BAK, function to promote apoptosis by regulating mitochondrial membrane potential. Anti-apoptotic BH2 proteins,
such as BCL2 and BCLxL, negatively regulate BAX and BAK, whereas a further group of these proteins, the BCL2homology domain-3 (BH3)-only proteins, control these survival proteins100. One of the key contributions of p53 to
apoptosis is the induction of the expression of genes that encode apoptotic proteins, functioning in both extrinsic and
intrinsic pathways. Many potential apoptotic target genes of p53 have been described, including those that encode the
BH3-domain proteins NOXA and PUMA. Deletion of many of the described apoptotic targets of p53 has little effect on
the sensitivity of the cell to stress-induced apoptosis, possibly reflecting the multitude of other apoptotic signals that
can be induced by p53. The dramatic effect that loss of PUMA has on the sensitivity of several different cell types to p53induced cell death is therefore particularly telling101,102, indicating that PUMA is a crucial mediator of apoptosis in
response to p53. Interestingly, PUMA has been proposed to function to release cytoplasmic p53 from inhibitory
interactions with anti-apoptotic BH3-domain proteins, allowing p53 to function in a transcriptionally independent
manner as a BH3-only protein103.
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Glucose
TIGAR
p53
AMPK
p21
Sestrins
Pentose phosphate
pathway
p53
Lower levels
of ROS
Survival
Survival
Pyruvate
Lactate
SCO2
p53
Mitochondrial respiration
Figure 3 | p53 and metabolism. Some of the points at which p53 can affect metabolic
pathways. This is a new and rapidly moving area of research, and the influence of p53 on
metabolism is likely to be much broader than illustrated here. In response to nutrient
stress, p53 can become activated by AMP kinase (AMPK), promoting cell survival through
an activation of the cyclin-dependent kinase inhibitor p21. Other functions of p53
include regulating respiration, through the action of SCO2, or in decreasing the levels of
reactive oxygen species (ROS), through the actions of TIGAR (Tp53-inducible glycolysis
and apoptosis regulator) or sestrins.
TIGAR
A gene that encodes a protein
that functions to lower
intracellular reactive oxygen
species levels by enhancing the
pentose phosphate pathway.
Pentose phosphate pathway
An alternative pathway for
glucose metabolism that
generates NADPH, which is
needed for the scavenging of
reactive oxygen species by
reduced glutathione.
Sestrins
A family of proteins that
modulate peroxide signalling
and regulate intracellular
reactive oxygen species levels.
Antioxidant functions. Another recently described
p53-inducible gene with a role in glycolysis is TIGAR
(Tp53-inducible glycolysis and apoptosis regulator)9,
which encodes a protein that shows some structural
similarity to the bisphosphatase domain of the bifunctional enzyme 6-phosphofructo-2-kinase/fructose 2,6
bisphosphate (PFK2/FBPase-2), and can lower the intracellular levels of fructose-2,6-bisphosphate. An effect of
TIGAR expression is therefore to decrease the activity
of 6-phospho-1-kinase, a key glycolytic enzyme, thereby
diverting the major glycolytic pathway into the pentose
phosphate pathway. The resultant increase in nucleotide
and NADPH production might have a number of interesting consequences, including an increase in glutathione
levels to promote scavenging of reactive oxygen species
(ROS). Although the apoptotic activity of p53 is mediated
— at least in part — through increasing ROS levels40,41, a
number of studies have shown a survival function for p53
in lowering intracellular ROS levels, involving the activity of p53-inducible genes such as TIGAR, sestrins42,43,
aldehyde dehydrogenase-4 (ALDH4)44, and others45
(FIG. 3). Most interestingly, this antioxidant function of
p53 is important in the absence of acute stress and acts
to prevent the accumulation of DNA damage in response
to day-to-day damage46. It is worth pointing out, however,
that even among these low-stress p53-response genes,
the sensitivity to p53 can differ. For example, SCO2 and
sestrin levels are reduced by the removal of p53 even
in unstressed cells, whereas basal TIGAR expression is
not so clearly affected. It seems likely that rather than
dividing into two discrete groups of genes that respond
to high stress and low stress, p53-responsive genes will
form a continuum that shows ever-increasing sensitivity
to p53 and stress levels (FIG. 4).
Based on current evidence, we can propose a model
in which p53 can have two important, but fundamentally
opposing, roles in response to stress (FIG. 4). The low levels
278 | APRIL 2007 | VOLUME 8
of DNA damage that are encountered during normal
life are dealt with, through p53, by lowering ROS levels
(and so reducing damage) and by promoting the survival
of the slightly damaged cell to allow repair (a process
to which p53 can also contribute). In response to more
severe, sustained stress — such as oncogene activation or
exposure to high doses of radiation — p53 switches from
promoting survival and repair to the induction of apoptosis12. This dual role of p53 might explain an interesting
paradox in the consequences of loss of PUMA, one of the
major mediators of p53-induced apoptosis mentioned
earlier. Whereas p53 is unable to induce apoptosis
in many cell types in the absence of PUMA, PUMAdeficient mice do not show enhanced tumour development20 — presumably because the tumour suppressor
functions of p53 in response to constitutive stress remain
intact (FIG. 4). However, knock-down of PUMA greatly
accelerates tumorigenesis in cells that have acquired
certain types of activated oncogene47 — probably because
the apoptotic response to eliminate damaged cells cannot
be activated. Of course, both activities of p53 (survival
and death) contribute to tumour suppression. The question that has not been fully explored yet is: are there
other consequences of loss of p53, apart from enhancing
cancer development?
Beyond cancer — other roles for p53
Most current models of how p53 functions in tumour
suppression evoke the stress-induced activation of p53,
which results in a block to further outgrowth cells that
have acquired some oncogenic potential. This reflects an
importance of several of the responses that are induced
by p53 (FIG. 1), including apoptosis, cell-cycle arrest,
maintenance of genomic stability and senescence48–50.
However, it is now becoming clear that the response
to p53 also influences several other aspects of life apart
from cancer development.
p53 in development. In vertebrates, the two other p53
family members, p63 and p73, illustrate a requirement
for at least some p53-like function during development16. These proteins are structurally similar to p53
(FIG. 2), especially in the core DNA-binding domain in
the centre of these proteins, and function as transcription factors that regulate a similar set of genes to p53.
Deletion of either p63 or p73 has severe effects on the
normal development of mice, and a number of human
developmental diseases have also been linked to mutations in p63 (REF. 51). Although loss of p63 and p73
can result in a predisposition to cancer development52,
neither protein has the profound tumour-suppressive
activity that is shown by p53. Simpler organisms, such
as flies or worms, carry only one p53 family member,
which has a role in stress-induced apoptosis in the
germline of these animals53. On a structural basis, p63
and p73 have been suggested to be evolutionarily more
ancient than p53, and the worm and fly p53 might
be more accurately described as p63 or p73 (REF. 54).
However, in these simple organisms the principal function of these p53 orthologues seems to be to protect the
germline from the effects of genotoxic damage.
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Low/constitutive stress
High/acute stress
p53 levels
Cell-cycle arrest
Anti-oxidant
DNA repair
Apoptosis
Cell survival
Prevention/repair of damaged cells
Tumour suppression
Development
Longevity
Cell death
Elimination of damaged cells
Tumour suppression
Radiation sickness
Ischaemia
Development
Ageing
Figure 4 | Regulation of life and death by p53. p53 functions in the response to both
the constitutive stress that is encountered during normal growth and development,
and to the acute stress signals that would be associated with oncogenic progression and
other types of trauma. In this model, p53 responds to conditions of low or constitutive
stress to play an important part in decreasing oxidative damage, and provides repair
functions to mend low levels of DNA damage. These activities of p53 contribute to
the survival and health of the cell as well as to the prevention of the acquisition
of tumorigenic mutations, and might contribute to overall longevity and normal
development. By contrast, acute stress that results in a more robust induction of p53
leads to the activation of apoptotic cell death and thereby the elimination of the
damaged cell. This function removes cells that have acquired oncogenic alterations, and
can contribute to neural tube closure during development, but carries accompanying
detrimental effects of stress-induced toxicity, such as radiation sickness,
neurodegenerative disease and premature ageing.
In light of the importance of p63 and p73 to normal
development in mice, it is perhaps not so surprising
that a closer analysis of the p53-null mice revealed
that they also show developmental abnormalities55.
Although many of these mice are normal at birth,
females of some strains show neural tube-closure
defects (or exencephaly) that reveals a role for p53 in
normal development, at least under certain circumstances56,57. This phenotype is also seen in mice with
defects in other components of mitochondrial death
pathways, which indicates that the lack of p53 leads
to a failure in progenitor cell apoptosis and so an
overproduction of neural tissue. Furthermore, studies
of developmental abnormalities induced by in utero
exposure to ionizing radiation clearly show that p53 has
a role in reducing the rate of birth defects56,58,59. Recent
studies in zebrafish demonstrate a protective function
of p53 against a broad range of early developmental
defects that are associated with loss-of-function mutations in genes as diverse as those involved in ribosomal
RNA synthesis60, DNA synthesis61, gut development62
and neuronal development63. These findings imply
that the normal p53 response constantly monitors the
early developmental process, presumably eliminating
the odd aberrant cell or killing the embryo when the
defects become too extreme58. Interestingly, p53 has a
clear anti-teratogenic function64,65, presenting a much
more tangible evolutionary advantage than the more
frequently studied anti-tumour activity and illustrating
an interesting parallel with the germline functions of
NATURE REVIEWS | MOLECULAR CELL BIOLOGY
p53 in lower organisms. It would be interesting to know
whether birth defects are more common in patients
with Li–Fraumeni syndrome, who carry a germline
mutation in one p53 allele and have an extremely high
incidence of cancer66.
The darker side of p53. Although suppression of
cancer or inhibition of teratogenesis are clearly desirable features of p53, the induction of p53 is not without
cost. Most clearly, p53 is strongly activated in response
to acute genotoxic stress such as is encountered following irradiation or chemotherapy, and the ensuing
apoptosis is responsible for the classic symptoms of
radiation sickness and side effects of cancer therapy.
It is also clear that other forms of stress or trauma,
not necessarily associated with potential malignant
progression, can also lead to the activation of p53. For
example, induction of p53 during ischaemia has been
shown to contribute to damage through the activation
of apoptosis, and a temporary inhibition of p53 function under these conditions might be highly beneficial
in the prevention and management of injury to the
liver, brain and kidneys67–69, or in treatment following
myocardial infarction70. A potential role for p53 in
immunity or the response to viral infection has also
been suggested23, although there is no clear indication
yet as to the mechanistic basis for this activity. Equally
tantalizing is the possibility that p53 plays a part in
neurodegenerative syndromes such as Parkinson’s
disease, Alzheimer’s disease and Huntington’s disease71.
In contrast to the positive role of p53 in protection
from cancer, each of these examples reflects a more
negative role for p53 in which induction of the p53
response causes, rather than solves, problems. The
concept that p53 has a darker side becomes even more
profound with the realization that despite its help in
protecting from cancer, p53 might also contribute to
many of the undesirable aspects of ageing (see below).
Taken together, it seems possible that we pay a high
price for the protection from tumour development that
is provided by p53.
The quest for eternal life — p53 and ageing. One of the
most interesting and provocative functions of p53 is
in the regulation of lifespan, although whether p53
helps or hinders the ageing process is not yet clear.
The observation that even a slight constitutive hyperactivation of p53 results in an alarming prematureageing phenotype in mice72,73 cast a dark cloud over the
enthusiasm for systemic activation of p53 as a cancer
therapeutic (BOX 2). In humans, a polymorphism in
p53 that results in a slight reduction in its activity is
associated with an enhanced cancer risk, but also with
increased longevity74. How p53 might promote ageing
is not yet clear, although a contribution of p53 to cellular senescence and the limitation of the proliferative
capacity of stem cells has been proposed75. In Drosophila
melanogaster, the extended lifespan that results from
a reduction of p53 activity in neurons is not further
enhanced by calorie restriction 76, which increases
longevity in a number of organisms from yeast to mice.
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Box 2 | p53 and therapy
The observation that p53 function is lost in most cancers makes it an attractive target for new therapies. Because p53 can
induce tumour cell death, the most actively explored avenue is to identify small molecules that will allow the reactivation
of p53 in cancers. For cancers that retain wild-type p53, but have suffered alterations that prevent the activation of p53, a
number of compounds have been described that target MDM2, an important negative regulator of p53 (REFS 94–
96,104–106). These include compounds such as Nutlin-3, which block the interaction of p53 with MDM2, and HLI98,
which directly target the ubiquitin-ligase activity of MDM2. Of course, these drugs are likely to activate p53 in both
normal and tumour cells, but the observation that cancers are much more sensitive to apoptotic stimuli than normal cells
raises the hope that these compounds will be sufficiently selective in their killing to be useful cancer therapeutics.
The cancers that have mutant p53 require a different approach, and compounds have been described that help some of
these mutant proteins refold to acquire at least some degree of wild-type function107,108. This is an attractive line of attack.
In most cases, only tumour cells express the mutant protein, and so such drugs are likely to be highly selective with low
toxicity to normal tissue. Another interesting approach it to try and selectively harness the fact that cancer cells lack p53,
and identify compounds that will only kill in the absence of p53 (so-called synthetic lethality).
Although activating p53 in cancer cells might be a good idea, there is also increasing interest in inhibiting p53 (REF. 109).
The obvious application for this approach would be to protect normal cells from the side effects of chemotherapy,
which are to a large extent a reflection of the apoptotic activity of p53 in the intestine and other proliferating tissues.
More generally, however, inhibitors of p53 might also be useful in preventing other detrimental effects of p53.
These results indicate that p53 functions in the pathways that respond to caloric restriction — such as those
involving silent information regulator-2 (SIR2) and/or
insulin signalling73,77. How these observations link to
the function of p53 as a survival factor in response
to glucose deprivation is not yet clear. Some of these
results also hint at a possible role for the recently identified N- or C-terminally truncated isoforms of p53
(REF. 78) in controlling ageing72,73. Regulation of glycolysis by p53 can also affect cellular, and so potentially
organismal, lifespan79.
However, despite the evidence that p53 can induce
premature ageing, it seems that this might not be a
function of properly regulated p53. Mice containing an
extra copy of the p53 gene, or with reduced expression
of Mdm2, showed the expected protection from tumour
development but no decrease in normal lifespan80,81.
Although not fully resolved, one explanation for
this apparent paradox is that the ageing phenotype
observed in the earlier studies reflects an imbalance
of p53 signalling, with the activation of some, but not
all, p53 functions82,83. Although some activities of p53
would be predicted to contribute to accelerated ageing, it seems equally possible that lack of p53, and the
associated enhanced oxidative stress, would also have
the same effect. Indeed, a deficiency of the p53-related
protein p63 has been shown to result in premature ageing that correlates with an induction of senescence34.
A recent study in the fruitfly has also indicated that
p53 is required for compensatory growth after tissue
damage and might contribute to tissue repair, cell
renewal and survival in other animals84. Indeed, mice
expressing altered forms of p53 also show perturbed
wound healing72. Taken together, is seems that perhaps
there is just no escape from our steady decline to the
Zimmer frame.
Can’t live with it — can’t live without it
The evidence that p53 has functions in addition to
responding to severe stress to prevent tumour development raises an interesting issue: if we look beyond
280 | APRIL 2007 | VOLUME 8
tumour suppression, is p53 good or bad for our health?
Is it possible that activation of p53 can be useful or
detrimental, depending on the extent or type of stress
signal that is being responded to? These questions
bring us back to the compelling evidence that p53activating signals function through different pathways
and that the response to p53 can vary depending on
cell type, environment and other contributing factors85.
More specifically, the switchable-p53 mice described
earlier33,86 provide a method to begin to explore some
exciting avenues for cancer therapies (BOX 2). These
studies show that delaying the induction of p53 until
after the effects of the irradiation have largely been
taken care of by other DNA-repair mechanisms protects the mice from the negative effects of p53-induced
apoptosis that are normally observed in radiosensitive
tissues. In other words, activation of p53 is responsible
for not only the inhibition of cancer outgrowth but
also for the debilitating toxic side effects of chemotherapeutic treatments in humans (FIG. 5). So perhaps
drugs that turn off p53 function could be used to protect normal tissues from the effects of chemotherapy,
allowing patients to tolerate much more aggressive (and
so potentially more successful) treatment regimes.
These mice might also allow us to delve more deeply
into the contribution of p53 to other aspects of health
and disease, if the premature death of these mice due
to cancer can be prevented by periodic, brief pulses of
p53 function. Given the large body of evidence that p53
can contribute to DNA repair11, it will be important to
understand whether p53 is truly irrelevant for a full
response to genotoxic damage or whether the antioxidant and repair functions of p53 can only cope with
much lower levels of damage than have been investigated so far in these studies. Although it seems that the
off switch in these mice is not absolutely complete86,
therefore raising the possibility that the basal functions of p53 might still be present in these animals, this
mouse model is perhaps the first of many that will allow
us to address the question of whether a reduction in p53
activity results in accelerated or delayed ageing.
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Acute genotoxic damage
Short-term
response
p53 off
No short-term
toxicity
p53 off
Tumour development
p53 on
Radiation
sickness
Long-term
response
p53 on
Tumour suppression
Figure 5 | Temporal regulation of p53 activity in response to DNA damage.
A recent study from Evan and colleagues33 provides evidence that the immediate
p53 response to DNA damage is detrimental and not necessary for tumour suppression.
The absence of p53 immediately after DNA damage protects animals from radiation
sickness, but does not prevent repair of the DNA damage. Persistent absence of p53
results in tumour development, as expected. However, even transient restoration of p53
activity after the resolution of the initial DNA damage can inhibit tumour development
without the deleterious responses, such as widespread apoptosis in lymphoid organs and
intestinal epithelium, that occur following the irradiation of mice with fully active p53.
These results suggest that the induction of p53 in response to signals that persist beyond
DNA damage, such as activated oncogenes, is the key to tumour suppression.
Functions of mutant p53
Just as wild-type p53 continues to surprise us by having
roles in a much broader range of processes than previously thought, interesting new activities for mutant
p53 are also being uncovered. Mutations in p53 are
extremely common in tumours, and at some point
during malignant progression about half of all cancers
acquire a mutation in p53 (REF. 87). It is clear that loss
of wild-type p53 function is vitally important for successful tumour progression, and that cancer-associated
mutations result in the loss of most of the normal functions of p53, such as transcriptional activation, cell-cycle
arrest and apoptosis.
p53 mutations in cancer. Mutations in p53 are different
from those that inactivate other tumour-suppressor genes
such as retinoblastoma (RB), in which only mutations
resulting in a loss of the wild-type protein are selected. In
the case of p53, many cancers retain expression of a p53
protein with only a single amino-acid change, which most
often occurs in the core DNA-binding domain, leading
to both the disruption of normal p53 function and the
accumulation of high levels of mutant p53 (REF. 87).
Many studies have indicated that the consequences of
expressing these mutant forms of p53 are not equivalent
to the simple loss of p53, and this is most clearly seen
in mouse models in which expression of mutant p53 is
strongly linked to a change in tumour spectrum and an
increase in metastatic potential compared to p53-null
mice88,89. How these mutant p53 proteins exert this
influence on tumour spread is now being explored, with
NATURE REVIEWS | MOLECULAR CELL BIOLOGY
evidence that they function by interfering with activities
of p63 or p73 (REF. 90). Although wild-type p53 shows
no obvious ability to bind p63 or p73, mutations in p53
can alter the protein’s conformation. This allows p53 to
bind its sibling proteins, resulting in an inhibition of
p63 and/or p73 function. In addition, mutant forms
of p53 acquire novel transcriptional activities that are
also likely to contribute to the enhanced malignant
potential of cells that express these proteins91,92.
p53 mutants in normal cells. Although mutant p53
affects cancer-cell behaviour, it is also interesting to
consider the consequences of mutant p53 expression in
otherwise normal cells. Although most humans develop
p53 mutations as somatic alterations in only a limited
number of cells, unfortunate individuals that suffer from
Li–Fraumeni syndrome carry a germline mutation in
p53 and express both a mutant form and wild-type form
of p53 in all tissues1. Patients with Li–Fraumeni syndrome show an extremely high incidence of many types
of cancer, in which the wild-type p53 allele is often lost.
However, the consequence of mutant-p53 expression
in normal somatic tissue is not yet clear.
Tissue-culture experiments have shown that mutant
p53 can function as a dominant-negative inhibitor
of wild-type p53. On the other hand, examination of
mouse or human cells in which only one p53 allele is
mutated indicate that under these conditions the mutant
p53 does not accumulate to the high levels it does in
cancers, and so does not efficiently block the activity
of the wild-type p53. Although this might initially suggest that having one mutant p53 allele has no effect in
normal cells, it is important to keep in mind that the
p53 pathway is exquisitely sensitive to small changes in
the levels or activity of p53, and that the patients with
Li–Fraumeni syndrome express only half the normal
amount of functional p53, regardless of any impact of
the mutant protein. So, although mutant p53 cannot
completely abolish wild-type p53 activity, there might
still be a small, but nevertheless important, shortcoming
in wild-type p53 activity in cells in which both wild-type
and mutant proteins are expressed.
The potential importance of what might seem to be
only slight changes in p53 regulation is further illustrated
by a polymorphism in the MDM2 promoter that results
in modest changes in the levels of the MDM2 protein,
one of the key regulators of p53 stability and function,
that can have a profound effect on an individual’s susceptibility to cancer93. Similarly in mice, even small
adjustments to MDM2 activity have clear effects on p53
(REF. 81). Polymorphisms in p53 itself can also results in
subtle, but potentially extremely important, differences
in activity 4. It seems that the p53 pathway needs only to
be slightly tweaked for an effect to be seen.
The anticipated consequences of any decrease in p53
activity would be a reduced resistance to cancer development, as is clearly seen in the patients with Li–Fraumeni
syndrome. But in the light of the newly discovered functions for p53, it is worth looking at these individuals more
closely. Are they exhausted unusually quickly during
exercise? If their cancer problems could be efficiently
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REVIEWS
dealt with in some way, would they be slower to age or
suffer less from neurodegenerative diseases? Might they
be more able to survive a stroke?
Conclusions and perspectives
The analysis of new mouse model systems might lead
us to the conclusion that we are better off without p53
if cancers can be held at bay. Several small-molecule
activators of p53 have been described, most of which
function to protect p53 from the negative regulatory
effects of MDM2 (REFS 94–96) (BOX 2). Because these
compounds are not genotoxic, they can induce p53 while
avoiding many of the deleterious side effects of conventional chemotherapies. A number of p53 inhibitors are
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Competing interests statement
The authors declare no competing financial interests.
DATABASES
The following terms in this article are linked online to:
OMIM: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=OMIM
Alzheimer’s disease | Huntington’s disease | Li–Fraumeni
syndrome | Parkinson’s disease
UniProtKB: http://ca.expasy.org/sprot
p53 | p63 | p73 | PFK2/FBPase-2 | SCO2
FURTHER INFORMATION
Karen H. Vousden’s homepage:
http://www.beatson.gla.ac.uk/research/index.html?topic_
id=36
David P. Lane’s homepage: http://www.imcb.a-star.edu.sg/
research/research_group/cell_cycle_control/6000000116_
article.html
Access to this links box is available online.
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© 2007 Nature Publishing Group