You are on page 1of 10



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.

The metabolic pathway through which glucose is metabolized to provide energy.

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: 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.

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
VOLUME 8 | APRIL 2007 | 275

© 2007 Nature Publishing Group

REVIEWS Hypoxia Telomere erosion Nutrient deprivation p53 Apoptosis Cell-cycle arrest Survival DNA repair Senescence Genomic stability DNA damage Ribosomal stress Oncogene activation Figure 1 | Activation and functions of 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. sporadic or severe stress. Undoubtedly there will be modifications. development and ageing is likely to depend on which cellular response is activated and on the context in which the activation occurs. Importantly. including an intriguing role of p53 in promoting survival37 as well as cell death. as seen in mammalian systems. different signals use different pathways to activate p53. 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. recent studies have revealed a hitherto unappreciated importance of p53 under conditions of apparently normal growth and development. stability and subcellular localization through the action of numerous other proteins that work directly or indirectly to restrain p53. 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. complications and caveats to this story. Control and release of p53 p53. such as acute genotoxic stress or oncogene activation. the everyday rigours of normal mammalian life can more systemically induce low levels of p53 activity. enzymes involved in post-translational modification of p53 (such as kinases and acetylases). but not DNA-damage-induced. 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. nutrient deprivation and hypoxia 23 (FIG. Although the importance of these responses to tumour suppression is clear. can have disastrous consequences to the survival of the organism. but is not necessary for the activation of p53 in response to DNA damage31. telomere erosion. Other equally compelling studies indicate that genotoxic stress is the key signal to activate p53 and tumour suppression in pre-cancerous lesions. transcriptional coactivators that can modulate the transcriptional activity of p53. And. p53 is extremely sensitive to even low levels of DNA damage. these signals do not all engage p53 through the same pathways. Ubiquitin ligase An enzyme that can transfer ubiquitin onto a protein. a small protein that binds and inhibits MDM2. p53 activation by everyday stresses Despite the clear importance of the negative regulation of p53 during normal cell growth. 34). So. Interestingly.nature. The studies show that p53 becomes important only after the bulk of the damage has been resolved. ARF. activation of p53 — is responsible for almost all the tumour-suppressor activity of p53 (REF. including the regulation of protein activity. the ribosomal protein L11 has a role in activating p53 in response to ribosomal stress without a requirement for ARF32. It has become evident that despite the many levels of negative regulation that are in place to restrain p53. Loss of these regulators. MDM2 A ubiquitin ligase that functions as an important negative regulator of p53. 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. many other signals can also activate p53. making it essential to hold p53 function in check during normal development. which can target the protein for degradation by the proteasome. and subsequent failure to rein in p53 . As the product of a p53-inducible gene. induction of p53 through these mechanisms seems to have a role in responses beyond cell-cycle arrest and apoptosis. through its cell-cycle-arrest and apoptotic activities. Similarly. and many more (as described in a number of excellent recent reviews5. including inappropriate cell proliferation driven by oncogene activation. 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. has an important role in signalling to p53 in response to some oncogenes.36. but use different signalling molecules to stabilize and activate p53. one of the key ubiquitin ligases responsible for limiting the levels of p53. However. These p53-regulatory proteins include ubiquitin ligases that have a role in controlling p53 protein stability. 1). The role of p53 in tumour suppression. A protein that belongs to the BCL2 family and that promotes mitochondrial outer membrane permeabilization and apoptosis. PUMA (p53-upregulated mediator of apoptosis). 22) (BOX 1). and that DNA damage can be induced by the activation of several oncogenes in an ARF-independent manner35. For example. a response that is thought to contribute to tumour suppression by either allowing for repair or by eliminating cells harbouring potentially oncogenic alterations. previously unanticipated contributions of these responses to other aspects of human health and disease are being uncovered.23–26). 276 | APRIL 2007 | VOLUME 8 © 2007 Nature Publishing Group www. 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. There is evidence that p53 can play a part in determining which response is induced through differential activation of target-gene expression. and so activate the transcriptionally independent apoptotic function of p53 (REF. and it is possible that different responses are induced by different stress signals. p53 is an integral part of the response to genotoxic stress28–30. Activation of p53 can result in a number of cellular responses. MDM2 functions in a negative-feedback loop with p53. This is nicely illustrated by MDM2. p53 has a key role in integrating the cellular responses (pink boxes) to different types of stress (blue boxes). Analysis of the p53 orthologue in flies and worms shows that. can have a strong inhibitory effect on cell growth. Multiple mechanisms exist to negatively control 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. Supporting this idea are studies showing that ARF — which is necessary for oncogene-induced.

which is required for the assembly of cytochrome c oxidase8. the BCL2homology domain-3 (BH3)-only proteins. functioning in both extrinsic and intrinsic pathways. function to promote apoptosis by regulating mitochondrial membrane potential. a mitochondrial protein that also contributes to efficient oxidative phosphorylation39. A family of proteins with structurally conserved domains. 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. and the position of the hotspots for these mutations are indicated by the orange lightning bolts. 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. and hitherto undetected. More surprisingly. p53 is subject to numerous post-transcriptional modifications. it predominantly seems to influence the intrinsic pathway. de-acetylases and de-ubiquitylating enzymes have been identified that can reverse most of these modifications. BAX and BAK.102. but could clearly have a much broader role in the response to metabolic stress. Interestingly. The dramatic effect that loss of PUMA has on the sensitivity of several different cell types to p53induced cell death is therefore particularly telling101. This triggers a cascade of events leading to caspase activation and cell death99. NATURE REVIEWS | MOLECULAR CELL BIOLOGY © 2007 Nature Publishing Group VOLUME 8 | APRIL 2007 | 277 . Similarly. although some isoforms of these p53 relatives also contain a C-terminal sterile α-motif (SAM) domain. possibly reflecting the multitude of other apoptotic signals that can be induced by p53. 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. and has been proposed to contribute to the short-term survival of cells suffering. However. Warburg effect An increase in aerobic glycolysis that is characteristic of cancer cells. known as the BCL2homology (BH) domains. One of the key contributions of p53 to apoptosis is the induction of the expression of genes that encode apoptotic proteins. negatively regulate BAX and BAK. because restoration of SCO2 expression in p53deficient cancer cell lines can restore mitochondrial respiration8. which responds to stress signals98. Deletion of many of the described apoptotic targets of p53 has little effect on the sensitivity of the cell to stress-induced apoptosis. Conversely. 3). Most of the point mutations found in naturally occurring cancers occur in the central DNA-binding domain. methylation and modification with ubiquitin-like proteins. and so the release of apoptogenic factors from the mitochondrial intermembrane space into the cytoplasm. indicating that PUMA is a crucial mediator of apoptosis in response to p53. This apoptotic pathway leads to a perturbation of mitochondrial membrane potential. p53-null mice get exhausted very quickly during exercise — presumably because they cannot efficiently generate energy through aerobic respiration8. acetylation. Metabolic stress that results in low glucose levels has been shown to activate p53 through a pathway that involves AMP kinase (AMPK). a dramatic increase in glycolysis — called the Warburg effect — might help solve this problem of sustained energy production. Interestingly. Anti-apoptotic BH2 proteins. Phosphatases. including those that encode the BH3-domain proteins NOXA and PUMA. 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. starvation38. roles for p53 in controlling different metabolic pathways under apparently normal growth conditions has also been recently described. One of the most dramatic responses to p53 is the induction of apoptosis. 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. Many potential apoptotic target genes of p53 have been described. These are the extrinsic pathway. which is induced through the activation of cell-surface receptors. including the N-terminal transactivation domains. Regulation of glucose metabolism. such as BCL2 and BCLxL. Two of these BH-domain proteins. a type of programmed cell death. including phosphorylation. Multiple isoforms of each of these proteins have now been described16. have a central role in the intrinsic apoptotic pathway. The resultant defect in respiration would affect tumour cells (which are all defective in some way for p53 activity) particularly strongly. that can affect the function and stability of p53. In cancers. and so provide a proliferative advantage to tumour cells that are attempting to Box 1 | Apoptotic pathways and p53 grow abnormally. defect in endurance. the central sequence-specific DNA-binding domain and the C-terminal regulatory domain. loss of p53 seems to be a root cause of the metabolic changes that characterize cancer cells. For example. because the abnormal and deregulated proliferation that is characteristic of cancer cells makes them particularly energy demanding. The p53-related proteins p63 and p73 show a similar overall structure.REVIEWS TransProline-rich activation domain p53 Phosphorylation Point mutations in tumours Phosphorylation Acetylation Methylation Ubiquitylation Neddylation Sumoylation Sequence-specific DNA-binding domain Oligomerization domain p73 SAM domain p63 Figure 2 | Structure of p53 family members. hopefully temporary. basal levels of p53 have been shown to have a role in regulating AIF expression. allowing p53 to function in a transcriptionally independent manner as a BH3-only protein103. whereas a further group of these proteins. PUMA has been proposed to function to release cytoplasmic p53 from inhibitory interactions with anti-apoptotic BH3-domain proteins. control these survival proteins100. This allows p53 to enhance oxidative phosphorylation. Although p53 has been implicated in both pathways. and the intrinsic pathway. p53 has been shown to induce the expression of the copper transporter SCO2. The major functional domains of the p53 protein are shown. Apoptotic signals can engage two main pathways (which are also interconnected). the loss of p53 activity in cells results in a reduction in oxygen consumption.

Sestrins A family of proteins that modulate peroxide signalling and regulate intracellular reactive oxygen species levels. sestrins42. through p53. and a number of human developmental diseases have also been linked to mutations in p63 (REF. Pentose phosphate pathway An alternative pathway for glucose metabolism that generates NADPH. Simpler organisms. 2). which has a role in stress-induced apoptosis in the germline of these animals53. Although the apoptotic activity of p53 is mediated — at least in part — through increasing ROS levels40. 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. 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. it is now becoming clear that the response to p53 also influences several other aspects of life apart from cancer development. This reflects an importance of several of the responses that are induced by p53 (FIG. and the worm and fly p53 might be more accurately described as p63 or p73 (REF. and others45 (FIG. Other functions of p53 include regulating respiration. 4). cell-cycle . In response to more severe. and can lower the intracellular levels of fructose-2. This dual role of p53 might explain an interesting paradox in the consequences of loss of PUMA.nature. through the actions of TIGAR (Tp53-inducible glycolysis and apoptosis regulator) or sestrins. Antioxidant functions. illustrate a requirement for at least some p53-like function during development16.REVIEWS Glucose AMPK TIGAR p53 Sestrins Pentose phosphate pathway Lower levels of ROS Survival p21 p53 Survival Pyruvate SCO2 p53 Lactate Mitochondrial respiration Figure 3 | p53 and metabolism. In response to nutrient stress. 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. Deletion of either p63 or p73 has severe effects on the normal development of mice. The question that has not been fully explored yet is: are there other consequences of loss of p53. However. p53 in development. On a structural basis. p53-responsive genes will form a continuum that shows ever-increasing sensitivity to p53 and stress levels (FIG. however. both activities of p53 (survival and death) contribute to tumour suppression. It is worth pointing out. 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). involving the activity of p53-inducible genes such as TIGAR. which is needed for the scavenging of reactive oxygen species by reduced glutathione. but fundamentally opposing.41. 3). the two other p53 family members. Some of the points at which p53 can affect metabolic pathways. and the influence of p53 on metabolism is likely to be much broader than illustrated here. Another recently described p53-inducible gene with a role in glycolysis is TIGAR (Tp53-inducible glycolysis and apoptosis regulator)9. However. This is a new and rapidly moving area of research. p63 and p73 have been suggested to be evolutionarily more ancient than p53. a number of studies have shown a survival function for p53 in lowering intracellular ROS levels. maintenance of genomic stability and senescence48–50. 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. Of course.6-bisphosphate. An effect of TIGAR expression is therefore to decrease the activity of 6-phospho-1-kinase. especially in the core DNA-binding domain in the centre of these proteins. 1). 4). Based on current evidence. However. aldehyde dehydrogenase-4 (ALDH4)44. TIGAR A gene that encodes a protein that functions to lower intracellular reactive oxygen species levels by enhancing the pentose phosphate pathway. For example. we can propose a model in which p53 can have two important. roles in response to stress (FIG.43. such as flies or worms.6 bisphosphate (PFK2/FBPase-2). Although loss of p63 and p73 can result in a predisposition to cancer development52. 54). The resultant increase in nucleotide and NADPH production might have a number of interesting consequences. and function as transcription factors that regulate a similar set of genes to p53. 278 | APRIL 2007 | VOLUME 8 © 2007 Nature Publishing Group www. Most interestingly. 4). one of the major mediators of p53-induced apoptosis mentioned earlier. which encodes a protein that shows some structural similarity to the bisphosphatase domain of the bifunctional enzyme 6-phosphofructo-2-kinase/fructose 2. neither protein has the profound tumour-suppressive activity that is shown by p53. Whereas p53 is unable to induce apoptosis in many cell types in the absence of PUMA. including an increase in glutathione levels to promote scavenging of reactive oxygen species (ROS). p53 can become activated by AMP kinase (AMPK). In vertebrates. whereas basal TIGAR expression is not so clearly affected. carry only one p53 family member. It seems likely that rather than dividing into two discrete groups of genes that respond to high stress and low stress. including apoptosis. PUMAdeficient mice do not show enhanced tumour development20 — presumably because the tumour suppressor functions of p53 in response to constitutive stress remain intact (FIG. or in decreasing the levels of reactive oxygen species (ROS). through the action of SCO2. in these simple organisms the principal function of these p53 orthologues seems to be to protect the germline from the effects of genotoxic damage. the sensitivity to p53 can differ. 51). thereby diverting the major glycolytic pathway into the pentose phosphate pathway. p63 and p73. which results in a block to further outgrowth cells that have acquired some oncogenic potential. These proteins are structurally similar to p53 (FIG. The low levels of DNA damage that are encountered during normal life are dealt with. SCO2 and sestrin levels are reduced by the removal of p53 even in unstressed cells. promoting cell survival through an activation of the cyclin-dependent kinase inhibitor p21. that even among these low-stress p53-response genes. a key glycolytic enzyme.

but carries accompanying detrimental effects of stress-induced toxicity. Furthermore. DNA synthesis61. A potential role for p53 in immunity or the response to viral infection has also been suggested23. Although suppression of cancer or inhibition of teratogenesis are clearly desirable features of p53. neurodegenerative disease and premature ageing. It is also clear that other forms of stress or trauma. which indicates that the lack of p53 leads to a failure in progenitor cell apoptosis and so an overproduction of neural tissue. although there is no clear indication yet as to the mechanistic basis for this activity.59.73 cast a dark cloud over the enthusiasm for systemic activation of p53 as a cancer therapeutic (BOX 2). and to the acute stress signals that would be associated with oncogenic progression and other types of trauma. presumably eliminating the odd aberrant cell or killing the embryo when the defects become too extreme58. and can contribute to neural tube closure during development. it seems possible that we pay a high price for the protection from tumour development that is provided by p53. Equally tantalizing is the possibility that p53 plays a part in neurodegenerative syndromes such as Parkinson’s disease. at least under certain circumstances56.58. Taken together. and might contribute to overall longevity and normal development. a polymorphism in p53 that results in a slight reduction in its activity is associated with an enhanced cancer risk. p53 might also contribute to many of the undesirable aspects of ageing (see below). 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. By contrast. The observation that even a slight constitutive hyperactivation of p53 results in an alarming prematureageing phenotype in mice72. Alzheimer’s disease and Huntington’s disease71. it is perhaps not so surprising that a closer analysis of the p53-null mice revealed that they also show developmental abnormalities55. Apoptosis Cell death Elimination of damaged cells Tumour suppression Radiation sickness Ischaemia Development Ageing Figure 4 | Regulation of life and death by p53. but also with increased longevity74. can also lead to the activation of p53. 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 © 2007 Nature Publishing Group VOLUME 8 | APRIL 2007 | 279 . and the ensuing apoptosis is responsible for the classic symptoms of radiation sickness and side effects of cancer therapy. 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. 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. rather than solves. although whether p53 helps or hinders the ageing process is not yet clear. The darker side of p53. This function removes cells that have acquired oncogenic alterations. p53 functions in the response to both the constitutive stress that is encountered during normal growth and development. females of some strains show neural tube-closure defects (or exencephaly) that reveals a role for p53 in normal development. which increases longevity in a number of organisms from yeast to mice. Although many of these mice are normal at birth. induction of p53 during ischaemia has been shown to contribute to damage through the activation of apoptosis. not necessarily associated with potential malignant progression.REVIEWS Low/constitutive stress High/acute stress p53 levels Cell-cycle arrest Anti-oxidant DNA repair Cell survival Prevention/repair of damaged cells Tumour suppression Development Longevity p53 in lower organisms. such as radiation sickness. 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. and a temporary inhibition of p53 function under these conditions might be highly beneficial in the prevention and management of injury to the liver. In light of the importance of p63 and p73 to normal development in mice. problems. 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 defects56.57. These findings imply that the normal p53 response constantly monitors the early developmental process. In Drosophila melanogaster. or in treatment following myocardial infarction70. This phenotype is also seen in mice with defects in other components of mitochondrial death pathways. How p53 might promote ageing is not yet clear. p53 has a clear anti-teratogenic function64. The concept that p53 has a darker side becomes even more profound with the realization that despite its help in protecting from cancer. the induction of p53 is not without cost. Most clearly. brain and kidneys67–69. In humans. In this model. Interestingly. p53 is strongly activated in response to acute genotoxic stress such as is encountered following irradiation or chemotherapy. who carry a germline mutation in one p53 allele and have an extremely high incidence of cancer66. p53 responds to conditions of low or constitutive stress to play an important part in decreasing oxidative damage. although a contribution of p53 to cellular senescence and the limitation of the proliferative capacity of stem cells has been proposed75.65. gut development62 and neuronal development63. One of the most interesting and provocative functions of p53 is in the regulation of lifespan. For example. the extended lifespan that results from a reduction of p53 activity in neurons is not further enhanced by calorie restriction 76. and provides repair functions to mend low levels of DNA damage. It would be interesting to know whether birth defects are more common in patients with Li–Fraumeni syndrome. The quest for eternal life — p53 and ageing.

it seems that this might not be a function of properly regulated p53. Regulation of glycolysis by p53 can also affect cellular. More generally. an important negative regulator of p53 (REFS 94– 96. 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). Of course. mice expressing altered forms of p53 also show perturbed wound healing72. 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.nature. Although some activities of p53 would be predicted to contribute to accelerated . p53 functions82. 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. or with reduced expression of Mdm2. However. In other words. despite the evidence that p53 can induce premature ageing. the most actively explored avenue is to identify small molecules that will allow the reactivation of p53 in cancers. a deficiency of the p53-related protein p63 has been shown to result in premature ageing that correlates with an induction of senescence34. which are to a large extent a reflection of the apoptotic activity of p53 in the intestine and other proliferating tissues. 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. So perhaps drugs that turn off p53 function could be used to protect normal tissues from the effects of chemotherapy. and so potentially organismal. inhibitors of p53 might also be useful in preventing other detrimental effects of p53. which block the interaction of p53 with MDM2. Although not fully resolved. environment and other contributing factors85. More specifically. For cancers that retain wild-type p53.or C-terminally truncated isoforms of p53 (REF.86 provide a method to begin to explore some exciting avenues for cancer therapies (BOX 2). these drugs are likely to activate p53 in both normal and tumour cells. brief pulses of p53 function. it seems equally possible that lack of p53.77. a number of compounds have been described that target MDM2. cell renewal and survival in other animals84. These include compounds such as Nutlin-3. would also have the same effect. and compounds have been described that help some of these mutant proteins refold to acquire at least some degree of wild-type function107. if the premature death of these mice due to cancer can be prevented by periodic. Indeed.REVIEWS Box 2 | p53 and therapy The observation that p53 function is lost in most cancers makes it an attractive target for new therapies. is seems that perhaps there is just no escape from our steady decline to the Zimmer frame. This is an attractive line of attack.108. 78) in controlling ageing72. and so such drugs are likely to be highly selective with low toxicity to normal tissue. showed the expected protection from tumour development but no decrease in normal lifespan80. The cancers that have mutant p53 require a different approach. and HLI98. and the associated enhanced oxidative stress. Because p53 can induce tumour cell death. 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. In most cases. there is also increasing interest in inhibiting p53 (REF. 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. Given the large body of evidence that p53 can contribute to DNA repair11.83. allowing patients to tolerate much more aggressive (and so potentially more successful) treatment regimes. only tumour cells express the mutant protein. Another interesting approach it to try and selectively harness the fact that cancer cells lack p53. Indeed. 109). therefore raising the possibility that the basal functions of p53 might still be present in these animals. 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. but not all. Although activating p53 in cancer cells might be a good idea. The obvious application for this approach would be to protect normal cells from the side effects of chemotherapy. however. lifespan79. 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. Mice containing an extra copy of the p53 gene. www.104–106). and identify compounds that will only kill in the absence of p53 (so-called synthetic lethality). Although it seems that the off switch in these mice is not absolutely complete86. 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 © 2007 Nature Publishing Group tumour suppression. but have suffered alterations that prevent the activation of p53. one explanation for this apparent paradox is that the ageing phenotype observed in the earlier studies reflects an imbalance of p53 signalling. Some of these results also hint at a possible role for the recently identified N.73.81. Taken together. is p53 good or bad for our health? Is it possible that activation of p53 can be useful or detrimental. How these observations link to the function of p53 as a survival factor in response to glucose deprivation is not yet clear. with the activation of some. which directly target the ubiquitin-ligase activity of MDM2. the switchable-p53 mice described earlier33. These mice might also allow us to delve more deeply into the contribution of p53 to other aspects of health and disease.

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. even small adjustments to MDM2 activity have clear effects on p53 (REF. The anticipated consequences of any decrease in p53 activity would be a reduced resistance to cancer development. with NATURE REVIEWS | MOLECULAR CELL BIOLOGY © 2007 Nature Publishing Group VOLUME 8 | APRIL 2007 | 281 . the consequence of mutant-p53 expression in normal somatic tissue is not yet clear. it is important to keep in mind that the p53 pathway is exquisitely sensitive to small changes in the levels or activity of p53. Are they exhausted unusually quickly during exercise? If their cancer problems could be efficiently Acute genotoxic damage Short-term response p53 off No short-term toxicity p53 on Radiation sickness p53 off p53 on Long-term response Tumour development Tumour suppression Figure 5 | Temporal regulation of p53 activity in response to DNA damage. cell-cycle arrest and apoptosis. but potentially extremely important. is the key to tumour suppression. 87). So. 87). even transient restoration of p53 activity after the resolution of the initial DNA damage can inhibit tumour development without the deleterious responses. In the case of p53. differences in activity 4. and that the patients with Li–Fraumeni syndrome express only half the normal amount of functional p53. such as widespread apoptosis in lymphoid organs and intestinal epithelium. p53 mutants in normal cells. 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. It is clear that loss of wild-type p53 function is vitally important for successful tumour progression. Mutations in p53 are different from those that inactivate other tumour-suppressor genes such as retinoblastoma (RB). Polymorphisms in p53 itself can also results in subtle. How these mutant p53 proteins exert this influence on tumour spread is now being explored. in which only mutations resulting in a loss of the wild-type protein are selected. that occur following the irradiation of mice with fully active p53. many cancers retain expression of a p53 protein with only a single amino-acid change. 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. However. interesting new activities for mutant p53 are also being uncovered. one of the key regulators of p53 stability and function. shortcoming in wild-type p53 activity in cells in which both wild-type and mutant proteins are expressed. it is worth looking at these individuals more closely.89.REVIEWS evidence that they function by interfering with activities of p63 or p73 (REF. These results suggest that the induction of p53 in response to signals that persist beyond DNA damage. mutations in p53 can alter the protein’s conformation. there might still be a small. Similarly in mice. In addition. such as activated oncogenes. and at some point during malignant progression about half of all cancers acquire a mutation in p53 (REF. it is also interesting to consider the consequences of mutant p53 expression in otherwise normal cells. 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. 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. regardless of any impact of the mutant protein. in which the wild-type p53 allele is often lost. This allows p53 to bind its sibling proteins. 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. that can have a profound effect on an individual’s susceptibility to cancer93. although mutant p53 cannot completely abolish wild-type p53 activity. Many studies have indicated that the consequences of expressing these mutant forms of p53 are not equivalent to the simple loss of p53. such as transcriptional activation. Tissue-culture experiments have shown that mutant p53 can function as a dominant-negative inhibitor of wild-type p53. But in the light of the newly discovered functions for p53. Although this might initially suggest that having one mutant p53 allele has no effect in normal cells. but does not prevent repair of the DNA damage. as is clearly seen in the patients with Li–Fraumeni syndrome. Although most humans develop p53 mutations as somatic alterations in only a limited number of cells.92. The absence of p53 immediately after DNA damage protects animals from radiation sickness. 90). Mutations in p53 are extremely common in tumours. However. p53 mutations in cancer. resulting in an inhibition of p63 and/or p73 function. which most often occurs in the core DNA-binding domain. but nevertheless important. Persistent absence of p53 results in tumour development. It seems that the p53 pathway needs only to be slightly tweaked for an effect to be seen. leading to both the disruption of normal p53 function and the accumulation of high levels of mutant p53 (REF. 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. and so does not efficiently block the activity of the wild-type p53. and that cancer-associated mutations result in the loss of most of the normal functions of p53. Patients with Li–Fraumeni syndrome show an extremely high incidence of many types of cancer. as expected. Although wild-type p53 shows no obvious ability to bind p63 or p73. 81). Although mutant p53 affects cancer-cell behaviour.

The C. H. 10. B. 307–315 (2006). Lapenko. 141–152 (2006). & Gartner. in contrast to 33 and 34. Oncogene 25. Bouchier-Hayes. Tumor suppressors: a developing role for p53? Curr. E.. F. F. U. temporary inhibition of p53 function in normal tissues might have a profound effect on reducing toxicity without further increasing the cancer risk. X. O. Cancer Cell 7. et al. Flores. M.. V. et al. Kortleverm. Cell Death Differ.. 41. L.. . & Clarke. A subset of p53-deficient embyos exhibit exencephaly. 307–315 (2004). Cepero. Of flies and men. Lassus. M. G. Control of cell migration: a tumour suppressor function for p53? Biol. 2091–2099 (2005). Nakamura. 86–91 (2004). & Deppert. 207–219 (2006). elegans homolog of the p53 tumor suppressor is required for DNA damage-induced apoptosis. M. 577–587 (2003). & Vousden. Pietsch. 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. J. Cell Biol. p53 ubiquitination: Mdm2 and beyond. A. Murray-Zmijewski. Nature 14. 13. Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4. Xia. Nature 408. Some p53binding proteins that can function as arbiters of life and death. L. et al. p53 regulates mitochondrial respiration. 25. 1027–1036 (2006). Hofmann. FEBS Lett. G. & Zhang. 121–134 (2006). Feinstein. would they be slower to age or suffer less from neurodegenerative diseases? Might they be more able to survive a stroke? also available21. Mol. 5.. Kaufman. J. & Wiesmuller. D. p53 in embryonic development: maintaining a fine balance. Hemann. Science 304. A. Efeyan. References 33 and 34 suggest that the response to oncogene activation. E. Cawley. 51. 32. et al. et al. Roger. Oncogene 18. a p53-induced modulator of autophagy. Yu. A global map of p53 transcriptionfactor binding sites in the human genome. H. A. Nordstrom. In Vivo.. Nature Med. M. Exp. D. Cell Death Differ. & Green. & Evan. A. Sci. A. More speculatively. J. C. 7. 38. 46. Surfing the p53 network.. 1278–1279 (2005). et al. PUMA couples the nuclear and cytoplasmic proapoptotic function of p53. 31.. I. Savior and slayer: the two faces of p53. A. 505–512 (2005). This paper provides evidence that loss of p53 might contribute to the Warburg effect. Cell 116. & Vogelstein. TIGAR. & Green. 5. J. Cell 18. Kubbutat. Harris. 52. Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs. The p53 pathway: what questions remain to be explored? Cell Death Differ. S. C. V. P. H. R. H. & Arakawa. Bensaad. K. Zhu. D. Ferrans.. L. Hu. I. Mol. et al. J. et al. 11848–11852 (1996). 13.. L. Kamijo. V. Guardian ancestry: fly p53 and damage-inducible apoptosis. 2. 2. J. J. M. K. U. show the importance of the DNA-damage signal to tumour suppression. & Iacopetta. & Levine. meiosis and stress resistance. Wei. K. 1317–1322 (2005). R. S. G.. E.. V. A.. P. Cell Death Differ. Nature Med. 10. 17. 19. R. Several small-molecule activators of p53 have been described. by inhibiting p53 and maintaining tumour suppression through the periodic reactivation of p53? Although some of these questions seem to be approaching fantasy.. & Prives. C. Levine. J.. et al. et al. K. Proc. Lowenstein. W. & Pietenpol. Biol. Ludwig. & Vousden. Sah. Armstrong. Cell. M. 591–595 (2001). Cancer Cell 3. & Hibner. 13. A.. G. Cell Death Differ. Newmeyer. No PUMA. 1602–1611 (2006). but not to DNA damage. & Bourdon. P. What has senescence got to do with cancer? Cancer Cell 7. M... T. Science 313. A.. Lane. 1722–1727 (2001). 631–636 (2005). Crighton. & Chumakov. & Brehm. PA26. bridge to the future. Wolff. M. 363–373 (2005). a tumour suppressor. M. p53 and disease: when the guardian angel fails. & Feng. The pathological p53-mediated response to DNA damage is distinct from p53-mediated tumor suppression. 107–120 (2006).. Lane. 172. J. Moll.. L.97. T. E. Chio. Nature 434. Opin. 214–217 (2006). 1306–1313 (2005).. 7.. Global investigation of p53-induced apoptosis through quantitative proteomic profiling using comparative amino acid-coded tagging. 907–913 (2005). V. 54. 951–961 (2006). Velasco-Miguel. 36. Cell 14. H. 37. M. most of which function to protect p53 from the negative regulatory effects of MDM2 (REFS 94–96) (BOX 2). 17. P.-X. D. p53 continues to surprise us. 34. Budanov. 159 (2006). 40. The p53 pathway: positive and negative feedback loops. Biol. Vogelstein. L. Barbieri. D. A demonstration of the antioxidant activity of basal levels of p53. X. 21. Cell Res. W. 36. Royds. 9333–9338 (2004). 695–706 (2006). 59. J. E. D. Genes Dev. 1650–1653 (2006). p53. Science 309. S. Nature Genet. DNA damage response as a candidate anti-cancer barrier in early human tumorigensis. Yee. 24. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. L. p63 and epithelial biology. Nature 434. A. 2140–2149 (2006). & Bernards. Brown Swigart. A. Biol. is crucial for p53-mediated tumour suppression. Marine. J. 15. Cell Death Differ. Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family. Christophorou. J. A. 6. Lowe. A number of p53 inhibitors are 1. Sutcliffe. S. W. D. Intrinsic tumour suppression. 22. P. An elegant study that consolidates the transcriptionally dependent and independent activities of p53 into a single model. 39. Suppression of tumorigenesis by the p53 target PUMA. Toeodoro. Nature 389.nature. A. Putzke. Kinzler. Regeneration of peroxiredoxins by p53-regulated sestrins. P. R. J. Nature 432. Transcription-independent pro-apoptotic functions of p53. Science 294. E. R. Dimri. 42. W.. A. 282 | APRIL 2007 | VOLUME 8 © 2007 Nature Publishing Group www. 248–249 (2003). Stambolsky. J. Garcia-Cao. 9. Oncogene 24. K. 57. Nature 443.. et al. 8. G. 16. 283–293 (2005). & Donehower. Gatz. 984–993 (2006). Cell 126. 127–137 (1999). & Finkel. 48. 596–600 (2004). 13. & Lu. Transcriptional regulation by p53: one protein. 28. Cell 124. P. Loss of the ARF tumor suppressor reverses premature replicative arrest but not radiation hypersensitivity arising from disabled atm function. Chromosomal stability.. 7. J. Mills. P. J. homologs of bacterial AhpD. E. 8. E. 38–47 (1999). A. High-frequency developmental abnormalities in p53-deficient mice. S. A. K. 16.. Sem. M. 11. 998–1008 (2006). Bensaad. 2464–2469 (1999). & Levine. 269–278 (1996). p53: link to the past. Cancer Res. is critical for apoptosis. Small-molecule inhibitor of p53 binding to mitochondria protects mice from γ radiation. A. Reactive oxygen species are downstream mediators of p53-dependent apoptosis. G. Developmental abnormalities induced by X-irradiation in p53 deficient mice. G. A. Jones. C. a p53-inducible regulator of glycolysis and apoptosis. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses.. Gu. & Serrano. Caenorhabditis elegans p53: role in apoptosis. Matoba. 1017–1026 (2006). Curr.. 11. M. Mol. 474–479 (2006). USA 101. Nature Cell Biol. Parker. no death: implications for p53-dependent apoptosis. Natl Acad. Johnson.. Cell 98. Nature Chem. Because these compounds are not genotoxic. Proteomics 3. 931–936 (1995). H. Genet. I. Ferlin. B.. 26. A. 29.. S. W. J. 27. Regulation of HDM2 activity by the ribosomal protein L11. Hanlon. J. Chipuk. Mol. et al. E. L. Velasco-Miguel. Ringhausen. K. Anti-apoptotic activity of low levels of wild type p53. 43. 13. Regulation of AIF expression by p53.. osteoblast-dependent osteoclastogenesis. EMBO J. & Evan. p53 functions as a negative regulator of osteoblastogenesis. 19. R. et al. 13. Sci. 1035–1038 (2000). M. & Vousden. Policing of oncogene activity by p53.. 927–934 (2006). L. Sablina.. 23. S. O. p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress. Bartkova. J. Wang. Hum. 877–884 (2006). R. L. or even in ageing. 50. J. A. Higgins. X. H. 47. 1003–1016 (2006). P. Del Sal. S.. Lohrum. Proc. T. Cancer Cell 4. Brooks. G. A. W. Yoon. Cell Death Differ. G. S. Koonin. D. p53 in recombination and repair. 11. B. But. 58. 20. 18. A. P. Sablina. 13. 14. Hall. et al. J. Science 312.. C. R. S. B. 55. Nature Genet. Herranz. T. 11. 44. & Rothman. Z. Natl Acad. J.REVIEWS dealt with in some way. et al. 49. 33. 30. Humbey. & Abrams. A. Polyak. is critical for suppression of tumorigenesis in Trp53 mutant mice. Derry. E. 215–221 (2002). 55. 2899–2908 (2005). in the absence of apoptosis. 864–870 (2005). S. Cancer Biol. M. 307–310 (2000). & Gu. 63–68 (2004). 175–180 (1995). Cell Death Differ. C. Baatout. L. Life Sci. 4566–4573 (1996). 134–140 (2004). B. 53. Curr. E. Carcinogenesis 26. 312. Cell 21. et al.. G. can we avoid the deleterious effects of p53 function in other pathologies. 499–509 (2004). K.. 962–972 (2006). et al. 59. et al. M. D. Biol. C. Curr. S. a novel target of the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genes. K. Cell Death Differ. Yu. Finch. R144–R147 (1997). A. Liu. Piette. Y. Polymorphisms in the p53 pathway. et al. 1732–1735 (2005). W. and bone remodeling. A model for p53-induced apoptosis. 4. A. 567. Zweier. 968–971 (2006). many possibilities. 12. 15. 45. -L. DRAM. A. 300–305 (1997). 3.. Strom. 13. CMLS Cell. D. & Roux. and judicious use of these drugs might allow us to switch p53 on and off in humans at will. they can induce p53 while avoiding many of the deleterious side effects of conventional chemotherapies. K. Gorgoulis. P. Boulton. Speidel. 7. Complicating the complexity of p53. & Lane. Kuwana. R. A. & Murphey. Y. Harrison. USA 93. Gadea. 115–125 (2006). W. When this might be advantageous will require further investigation in model systems. et al. Cell Biol. p53-mediated inhibtion of angiogenesis through upregulation of a collagen prolyl hydroxylase. A. J. 35. Two studies that. 49. J. T. Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Donehower. it seems that in the treatment of p53-null tumour cells with high doses of chemotherapy. et al. Braithwaite. 13. The p53-deficient mouse: a model for basic and applied cancer studies.. The antioxidant function of the p53 tumor suppressor gene. 56. Z.

J. et al. et al. B.. 14734–14739 (2002). 577–580 (1996). et al. blocks p53-HDM-2 interaction and activates p53 function in tumors. Cardiovasc. G. A teratologic suppressor role for p53 in benzo(a)pyrene-treated transgenic p53-deficient mice.beatson. Restoration of the tumor suppressor function to mutant p53 by a lowmolecular-weight compound. C. Proc. 97. & Kondo. 177–185 (2005). Katsuki. 104. W. Gerontol. Tyner.. J. Com. Plaster. 88. S. 181–187 (1995). et al. 6225–6235 (2002). 95. 107. E. 61. D.html Access to this links box is available online. et al. J. References 80 and 81 show that increasing the copy number of p53 while maintaining normal control over expression does not result in enhanced research/research_group/cell_cycle_control/6000000116_ article. Danial. S. 78. S. & Lu. 2063–2068 (2005). 547–559 (2005). 81. L. Competing interests statement The authors declare no competing financial interests. Foster. C. M. Temporal diffection of p53 function in vitro and in vivo. 1036–1038 (2003). et al. H. M. Cancer Cell 4. K. C. A. S. A. Sci.. 102. I. Vousden. Yoshida. M. H. J. J. 16. Coffey. J. 70. 127. B. R. G. Biol. et al. K. Cell death: critical control points. & Korsmeyer. 90. E. 20. W. 36. & Johnston. 647–656 (2002). 60. A. 1733–1737 (1999). Y. L. 861–872 (2004). et al. van Heemst. I. 726–736 (2005). Wells. p53 isoforms can regulate p53 transcriptional activity. P. Lett. R. 82. 84. 13309–13316 (2006).. Nature Med. 21. K. A.gla. Modulation of mammalian life span by the short isoform of p53. et al. H. 103. Norimura. Cory. G. I. Genes Dev. Science 285. Invest. 93. L. Bond. J. Genes Dev. Cell 119. C. Biol. Mutat. B. F. 72. Med. L. Lane’s homepage: http://www. Hum. Nature Med. Cancer Res. Z. 10..imcb. 20. Cell Death Differ. Bioenerg. Nature 415. Cell 116. P. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy..expasy. J. In vivo activation of the p53 pathway by small-molecular antagonists of MDM2. Vousden’s homepage: http://www. T. D. B. Nature Genet. Transcriptional activities of mutant p53: when mutations are more than a loss.. p53 mutation heterogeneity in cancer. Soc. Chem.REVIEWS 60. Structure-based design of potent nonpeptide MDM2 inhibitors. Curr. Green. 1606–1615 (2006). M. S. Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. & Lozano. 99. Cell Biochem. Com. are tumor resistant and age normally. Genes p53 | p63 | p73 | PFK2/FBPase-2 | SCO2 FURTHER INFORMATION Karen H. Biochem. & Deppert. Chen. Azuma. 69. J. & Clavien. N. & Helfand. Glatt-Deeley. M. 844–848 (2004).nlm. N. 68. 37. p53 deficiency rescues apoptosis and differentiation of multiple cell types in zebrafish flathead mutants deficient for zygotic DNA polymerase δ1.. 93. Y. Cell 119. 83. 75. S. 319–323 (2004). 13. P. E. 331. 71.. Morin. 1685–1686 (2005). X. 313–320 (2003). & Perry.. & Komarova. 67. A. A single nucleotide polymorphism in the Mdm2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans.ncbi. Unleashing the power of p53: lessons from mice and men. 718–726 (2005). Kim. New tricks of an old molecule: lifespan regulation by p53. 695–698 (1998). V. Vousden. Germline TP53 mutations and Li– Fraumeni syndrome.. 594–604 (2002). 281. Targeted deletion of p53 prevents cardiac rupture after myocardial infarction in mice. 106. Varley. The description of a small-molecule inhibitor of p53 98. Cell Cycle 3. et al. “Super p53” mice exhibit enhanced DNA damage response.4-benzodiazepine-2. & Adams. Des. R. 347–352 (2004).. 89. Perturbation of rRNA synthesis in the bap28 mutation leads to apoptosis mediated by p53 in the zebrafish central nervous system. 11–15 (2005). Science 302. R. Mendrysa. 97. & Dawid. Science 286. Maier. Poyurovsky. J. Science 309. 457–465 (2006). 223–235 (2006). 100. Biophys. 92. R. 65. D. M. Neurochem. et al. J. Gain-of-function of a p53 hot spot mutation in a mouse model of Li–Fraumeni syndrome. 73. Parks. 10130–10131 (2005). S. Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. One of a number of studies describing smallmolecule activators of p53. 65.. Am. S. E. Soussi. 16–21 (2006). S. Apoptotic pathways: the roads to ruin. Nature Rev. p53 mutant mice that display early ageing-associated phenotypes. 66. et al. 86. Bioog. Bykov. M. Prospective therapeutic applications of p53 inhibitors. F. 105. et al. E.nih. Christophorou. p53 and PUMA: a deadly duo. Toyama. The Bcl2 family: regulators of the cellular life-or-death switch. F. C. Cancer Cell 7. R. Natl Acad. Chem. N. 1571–1584 (2006). Jacobs. p53. 76. & Well. Abrams. 40. 834–842 (2005).. Mutant p53 gain-of-function in two mouse models of Li–Fraumeni syndrome. J. Dagher. Yang. 108. Clin. Poon. C. Olive. Issaeva. Blocking the path to death: anti-apoptotic molecules in ischemia/reperfusion injury of the liver. USA 99. 2122–2137 (2005). 321–328 (2003). G. 591–602 (2004). Differentiation of Hdm2-mediated p53 ubiquitination and Hdm2 autoubiquitination activity by small molecular weight inhibitors. 2911–2921 (2006). & Hammerschmidt. Biophys. Curr. Laposa. NATURE REVIEWS | MOLECULAR CELL BIOLOGY © 2007 Nature Publishing Group VOLUME 8 | APRIL 2007 | 283 . Gudkov. et al. P. and cancer. Aging Cell 5. B. 94. 6788–6793 (2000). 10. K. J. D. Harrison. 62. H. 66. P. Garcia-Cao. 79. H. Exp. M. M. A. Gimelshtein. et al. Protection against ischemic brain injury by inhibition of mitochondrial oxidative stress. W. D. A. & Prives. stem cells. Biomembr. 306–319 (2004). S. & Rotter. J. Neurochem. 96. S. Glycolytic enzymes can modulate cellular lifespan. Kondoh. Cancer 2. Graf. & Miller. Enhanced pharmacokinetic properties of 1. Tumor suppression by p53 without acceletated aging: just enough of a good thing? Cell Cycle 5. 506–509 (2004). 21. Compensatory proliferation in Drosophila imaginal discs requires Dronc-dependent p53 activity. Dahm. Georgiev. 74. E. Bourdon. 847–860 (2004). Res. et al. Telomeres. J.a-star. 64. M. & DePinho. Apoptosis in ischemic renal injury: roles of GTP depletion and p53. E.. p53-dependent apoptosis suppresses radiation-induced teratogenesis. et al. Nomoto. V. 63. 19. 12. Bauer.. Jeffers. J. 2507–2510 (1999). Neuronal expression of p53 dominant-negative proteins in adult Drosophila melanogaster extends life span. 160–168 (2004). N. 18. V. A. Irwin. 437–440 (2006). G. R. DATABASES The following terms in this article are linked online to: OMIM: http://www. 2900–2911 (2005). Villunger. M. G. et al. Komarov. 77. Res. M. Genes Dev. Busse. Live or let die: the cell’s response to p53. 113. Cell 119.and drug-induced apoptotic responses mediated by BH3-only proteins Puma and Noxa. Lai. Bauer.html?topic_ id=36 David P. Nature Rev. D. L. Small molecule RITA binds to p53. et al. T. Pharm. Nature Genet. Kaplan. Science 303. H. J. Mendrysa. N. 2. 85. Puma is an essential mediator of p53-dependent and-independent apoptotic pathways. M. Cancer 2.. 109. The p53 family in nervous system development and disease. 205–219 (2004). Cancer Res. Gondo. et al. V. P. J. 1321–1328 (2004). A. Curr. Matsusaka. Vassilev. 1423–1440 (2006). H. et al. J. Fiskum. et al. Pharmacological rescue of mutant p53 conformation and function. 19. M. A. fcgi?db=OMIM Alzheimer’s disease | Huntington’s disease | Li–Fraumeni syndrome | Parkinson’s disease UniProtKB: http://ca. 15. Variation in the human TP53 gene affects old age survival and cancer mortality. Sharpless.5-dione antagonists of the HDM2–p53 protein–protein interaction through structure-based drug design. Zebrafish lacking Alzheimer presenilin enhancer 2 (Pen-2) demonstrate excessive p53-dependent apoptosis and neuronal loss. 16. 3310–3314 (2006). 282–288 (2002). Campbell. 45–53 (2002). J. Loss of function of def selectively upregulates ∆113p53 expression to arrest expansion growth of digestive organs in zebrafish. Genes Dev. Laver. 70. Nature Med. Res. EMBO J. C. R. A. Family feud in chemosensitivity: p73 and mutant p53. Two sophisticated studies showing the effects of expression of mutant p53 in mouse models. & Rastinejad. 125–131 (2006). H. 878–886 (2004). senescence. et Cell 94. 714–717 (2006). L. L. Biol. Kidney Int. et al. N. Chem. 8. P. T. 96. 331. Sigal. Tumor suppression and normal aging in mice with constitutively high p53 activity. 91. & Helfand. et al. 101. Lang. A. 80. 87. Sonntag.