Cancer is a genetic pathology that arises in the adult tissues
of long-lived organisms, such as vertebrates, whose tis-
sues retain a substantial regenerative capacity throughout
life and, consequently, whose somatic cells accumulate
mutations. Occasionally, such mutations corrupt the
regulatory mechanisms that suppress untoward somatic
cell proliferation, survival and migration, resulting in the
progressive outgrowth of a somatic clone. Fortunately,
however, abundant evidence indicates that both the gen-
esis and evolution of cancers are actively restrained by
various tumour suppressive mechanisms.
Effective tumour suppression requires sensors that
accurately discriminate between normal and neoplas-
tic cell growth — allowing the former and forestalling
the latter. p53 is the poster child for such selectivity:
its potent growth suppressive functions are unleashed
only in damaged or transformed cells. Moreover, the
tumour suppressive action of p53 is remarkably eclec-
tic and versatile: there is strong selection against p53
pathway function in almost all cancers, irrespective
of the cell type or underlying oncogenic mechanism.
However, what signals trigger p53 activity during car-
cinogenesis, how diverse these signals are, and when
and for how long during tumour evolution such signals
are present are all unknown. Is p53 triggered by some
unitary, obligate attribute that is common to cancers of
all types or by many distinct signals that, between them,
encompass the range of aberrant processes in each dif-
ferent type of cancer? Is tumour suppression a discrete,
evolved function of vertebrate p53 or is it merely an
adaptation of the other known and venerable roles of
p53 in stress and damage responses? Answers to these
questions are important for several reasons. Knowing
how p53 discriminates between normal and tumour cells
might point to attributes of cancer cells that qualitatively
distinguish them from normal somatic cells and could
be used as tumour-specific targets. Knowing what sig-
nals drive selection for loss of p53 function in cancers
would help us understand what constrains and dictates
the varied trajectories of cancer evolution in different
tissues and individuals. Understanding when p53 is
triggered during tumorigenesis would indicate whether
p53 pathway inactivation is required only transiently
at some specific bottleneck in tumour evolution or if it
is a persistent requirement of cancers — in which case,
restoring p53 function would be therapeutically useful.
Identifying which of the many biological functions of
p53 are required to forestall tumorigenesis is essential
for improving the therapeutic efficacy of p53 restoration
in the treatment of cancers.
p53 and cancer — how, why, when and where?
Mammalian p53 family proteins — p53, p63 and p73
— are descendents of an evolutionarily ancient family
of transcription factors, the origins of which predate
the cnidarian–bilaterian divergence approximately 700
million years ago1 and may go back as far as the 2 bil-
lion year-old divergence of animalia and fungi2. Of the
three mammalian p53 family proteins, p53 is unique in
its pre-eminence as a tumour suppressor. In addition
p53 coordinates diverse cellular responses to stress and
damage and plays an emerging part in various physio
logical processes, including fertility3, cell metabo-
lism4 and mitochondrial respiration5, autophagy6, cell
Department of Pathology
and Helen Diller Family
Comprehensive Cancer Centre,
University of California San
Francisco, 513 Parnassus
Avenue, Room HSW‑450A,
UCSF Box 0502,
San Francisco, California
Correspondence to G.I.E.
24 September 2009
Cinidarians comprise an animal
phylum of ~9,000 radially
symmetrical, mostly marine
organisms. Most other animals
are bilaterally symmetrical
and are classed as bilateria.
The cnidarians and bilaterians
last shared a common ancestor
~570–700 million years ago.
p53 — a Jack of all trades
but master of none
Melissa R. Junttila and Gerard I. Evan
Abstract | Cancers are rare because their evolution is actively restrained by a range of tumour
suppressors. Of these p53 seems unusually crucial as either it or its attendant upstream or
downstream pathways are inactivated in virtually all cancers. p53 is an evolutionarily ancient
coordinator of metazoan stress responses. Its role in tumour suppression is likely to be a
relatively recent adaptation, which is only necessary when large, long-lived organisms
acquired the sufficient size and somatic regenerative capacity to necessitate specific
mechanisms to reign in rogue proliferating cells. However, such evolutionary reappropriation
of this venerable transcription factor entails compromises that restrict its efficacy as a
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© 2009 Macmillan Publishers Limited. All rights reserved
Interference of one
transcriptional activator by
another is called squelching,
and is caused by competition
for binding a scarce factor.
adhesion7, stem cell maintenance8 and development9.
In normal, unstressed cells, p53 activity is maintained
at low levels through a combination of p53 degradation
and direct transcriptional squelching, principally medi-
ated by the MDM2 E3-ubiquitin ligase and the related
protein MDM4 (also known as MDMX). such basal,
low-level p53 seems sufficient to mediate many, if not
all, of the physiological functions of p53 (FIG. 1). by con-
trast, oncogenic signalling and stress or damage signals
elicit a marked increase in p53 activity — mostly by hin-
dering its interactions with MDM2 and MDM4, which
triggers p53 accumulation and unleashes its transcrip-
tional activity. Intriguingly, the rapid post-translational
regulation of p53 activity by modulating its interactions
with MDM2 and MDM4 is a peculiarly vertebrate inven-
tion: no direct counterparts of MDM2 or MDM4 exist in
invertebrates, and invertebrate p53 homologues lack the
key residues with which these proteins interact10,11.
the extent to which the roles of p53 in tumour
suppression, stress or damage responses and normal
physiology in vertebrates are interdependent or overlap
mechanistically is unclear, and we can only guess at the
nature of the primordial function of p53 or when and
why during its evolution it acquired its many attributes
(BOX 1). A more detailed exposition of the tortuous phy-
logeny of p53 is dealt with elsewhere. Our specific inter-
est here is in ascertaining the extent to which the unique
evolutionary trajectory of p53 may have constrained or
embellished its capacity to act as a tumour suppressor
the ancient and evolutionarily conserved role of p53
as a mediator of DnA damage responses, together with
the dramatic genome instability and aneuploidy shown
by many p53-deficient cancer cells12–14, has fostered the
celebrated ‘guardian of the genome’ concept that p53
suppresses cancer principally by preserving genome
integrity, permanently crippling somatic cells that sus-
tain DnA damage and so preventing the accumulation of
oncogenic mutations. the idea has been further fuelled
by evidence that oncogenic signalling can, at least in some
circumstances, directly induce genomic damage15 and by
initial evidence for habitual DnA damage in early, pre-
malignant neoplastic lesions in humans16,17. Activation of
p53 by DnA damage is principally mediated through an
array of post-translational modifications18, pre-eminent
of which are the direct phosphorylation of p53 and its
principal regulators MDM2 and MDM4 through the
ataxia–telangiectasia mutated (AtM)–CHK2 or ataxia–
telangiectasia and rad3-related (Atr)–CHK1 kinase
pathways. this phosphorylation impairs interactions
between p53 and MDM2 and MDM4, inhibiting the
capacity of MDM2 and MDM4 to suppress p53 tran-
scription and promote p53 degradation. DnA damage
also elicits p53 acetylation and methylation, although the
functional roles of these modifications in determining
p53 activity are less clear.
Although DnA damage is a potent trigger of p53
activity, its role as the principal axis of p53-mediated
tumour suppression has recently been challenged by
evidence suggesting that the p53-mediated DnA dam-
age response and p53-mediated tumour suppression are
independent and separable p53 functions. Christophorou
et al. developed a mouse in which the endogenous Trp53
gene is modified to encode a p53–oestrogen receptor
fusion protein (p53ErtAM) that is only functional in
the presence of a synthetic ligand 4-hydroxytamoxifen
(4-OHt)19. because endogenous p53 function in such
Trp53ERTAM knock-in animals can be rapidly and revers-
ibly toggled between inactive and active by the systemic
administration of 4-OHt ligand, these mice can be used
to probe when during tumour evolution p53 function
is required for tumour suppression. these authors then
investigated the function of p53 in a lymphoma genesis
model induced by γ-radiation, a prototypical DnA
damage and p53-activating carcinogen. when p53 was
in its functional state, irradiation of mice triggered the
expected gamut of radiation pathologies, inducing wide-
spread p53-dependent apoptosis in radiosensitive tissues,
such as bone marrow, lymphoid organs and the gastro-
intestinal tract. After recovery from this acute radiation
injury p53 function was then deactivated and the tumour
incidence was monitored. remarkably, the mice showed
no protection from lymphomagenesis compared with
animals in which p53 function had never been restored.
the widespread p53-dependent apoptosis induced by
DnA damage in the lymphoid organs therefore made no
contribution to tumour suppression — the mice shared
all of the pain but none of the gain. by contrast, mice in
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822 | nOvEMbEr 2009 | vOlUME 9
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The authors thank the Ellison Medical Foundation for support.
Melissa R. Junttila is the Enrique Cepero, Ph.D. Fellow of the
Damon Runyon Cancer Research Foundation.
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
NCI Nature Protein Interaction Database (PID):
ATM | ATR | BMI1 | CBX7 | CHK1 | CHK2 | DMP1 | HRAS |
MDM2 | MDM4 | MYC | p14ARF | p19ARF | p53 | p63 | p73 | TBX2
Gerard Evan’s homepage:
International agency for Research on cancer (IaRc) Tp53
all links are aCtive in the Online Pdf
nAtUrE rEvIEws | CanCer
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