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Apoptosis La Red de p53

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Commentary 4077

Apoptosis – the p53 network


Susan Haupt1, Michael Berger2, Zehavit Goldberg2 and Ygal Haupt2,*
1Department of Pharmacy, and 2Lautenberg Center for General and Tumor Immunology, The Hebrew University Hadassah Medical School,
Jerusalem 91120, Israel
*Author for correspondence (e-mail: haupt@md.huji.ac.il)

Journal of Cell Science 116, 4077-4085 © 2003 The Company of Biologists Ltd
doi:10.1242/jcs.00739

Summary
Exposure to cellular stress can trigger the p53 tumor converge through Bid, which is a p53 target. The majority
suppressor, a sequence-specific transcription factor, to of these apoptotic effects are mediated through the
induce cell growth arrest or apoptosis. The choice between induction of specific apoptotic target genes. However, p53
these cellular responses is influenced by many factors, can also promote apoptosis by a transcription-independent
including the type of cell and stress, and the action of p53 mechanism under certain conditions. Thus, a multitude of
co-activators. p53 stimulates a wide network of signals that mechanisms are employed by p53 to ensure efficient
act through two major apoptotic pathways. The extrinsic, induction of apoptosis in a stage-, tissue- and stress-signal-
death receptor pathway triggers the activation of a caspase specific manner. Manipulation of the apoptotic functions of
cascade, and the intrinsic, mitochondrial pathway shifts the p53 constitutes an attractive target for cancer therapy.
balance in the Bcl-2 family towards the pro-apoptotic
members, promoting the formation of the apoptosome, and
consequently caspase-mediated apoptosis. The impact of Key words: p53, Apoptosis, Caspase, Mitochondria, Transcriptional
these two apoptotic pathways may be enhanced when they activation

Introduction nucleotide depletion (reviewed by Giaccia and Kastan, 1998).


The prevention of cancer is profoundly dependent on the p53 p53 activation involves stabilization of the protein, and
tumor suppressor protein. The ability of p53 to eliminate enhancement of its DNA binding and transcriptional activity.
excess, damaged or infected cells by apoptosis (Kerr et al., These changes in p53 are mediated by extensive post-
1972) is vital for the proper regulation of cell proliferation in translational modifications of p53 and protein-protein
multi-cellular organisms (Huang and Strasser, 2000). p53 is interactions with cooperating factors. Ultimately, the activation
activated by external and internal stress signals that promote of p53 leads to cell growth arrest, senescence or apoptosis, the
its nuclear accumulation in an active form. In turn, p53 induces choice of which depends on the summation of the incoming
either viable cell growth arrest or apoptosis. The latter activity signals and the cellular context (see below). Because the
is crucial for tumor suppression. The growth inhibitory apoptotic function of p53 is critical for tumor suppression,
activities of p53 prevent the proliferation of cells with damaged reconstitution of inactive p53-dependent apoptotic pathways is
DNA or with a potential for neoplastic transformation. In an attractive approach currently being explored for anti-cancer
addition, p53 contributes to cellular processes such as treatment. Here, we review recent developments in our
differentiation, DNA repair and angiogenesis, which also understanding of p53-mediated apoptosis. References to
appear to be vital for tumor suppression (reviewed by Vogt relevant exhaustive reviews on this subject are made in the
Sionov and Haupt, 1999). appropriate sections.
Being a key player in the cellular response to stress, p53
serves as the major obstruction for tumorigenesis. This
obstacle has to be removed in order to allow tumor Growth inhibition by p53: cell cycle arrest or
development. Indeed, approximately 50% of human cancers apoptosis?
bear p53 gene mutations; in the majority of the remaining p53 is a transcription factor that activates vital damage-
cancer cases, p53 activity is compromised by alternative containment procedures to restrict aberrant cell growth in
mechanisms (Vogelstein et al., 2000). These involve elevation response to DNA damage, oncogene activation, hypoxia and
in the expression levels of p53 inhibitors, such as Mdm2 or the the loss of normal cell contacts (Giaccia and Kastan, 1998;
E6 protein of HPV, or silencing of key p53 co-activators, such Lohrum and Vousden, 1999). It restricts cellular growth by
as ARF (Vogelstein et al., 2000; Vogt Sionov et al., 2001). inducing senescence, cell cycle arrest (at G1 and/or G2 phase)
Under normal conditions p53 is a short-lived protein. The or apoptosis (Jin and Levine, 2001). The exact criteria that
p53 inhibitor Mdm2 (Hdm2 in humans) is largely responsible influence p53 to stimulate cell cycle arrest or apoptosis are only
for keeping p53 in this state. Mdm2 inhibits the transcriptional partially understood and are the subject of intense study.
activity of p53 and, more importantly, promotes its degradation Several general factors that influence this decision include p53
by the proteasome. However, the status of p53 is drastically expression levels, the type of stress signal, the cell type and the
altered when cells are exposed to stress, including DNA cellular context at the time of exposure to stress (reviewed by
damage, untimely expression of oncogenes, hypoxia and Balint and Vousden, 2001; Vogt Sionov and Haupt, 1999).
4078 Journal of Cell Science 116 (20)
Several intriguing observations have recently provided insight The Myc protein has been implicated as an important
into the apparent intricacies of such cell fate determination. determinant of the choice between p53-induced growth arrest
The examples described below involve the binding of p53 to or apoptosis. Myc inhibits growth arrest in response to UV
its canonical binding sequence in target genes (el-Deiry et al., light, γ-irradiation and DNA damage inflicted by reactive
1992). Note, however, that p53 can also activate target genes oxygen species (Sheen and Dickson, 2002; Vafa et al., 2002).
through a non-canonical sequence. The first such example is in In the absence of Myc, cells that are exposed to UV light arrest
the p53-induced gene 3 (PIG3), which has been implicated in in a p53- and Miz-1 (DNA-binding Myc-interacting zinc-finger
the accumulation of reactive oxygen species and apoptosis 1)-dependent manner through activation of p21. However,
induction (Polyak et al., 1997). PIG3 can be induced by p53 when Myc is present, exposure to UV triggers its recruitment
through a microsatellite sequence within its untranslated region by Miz-1 to the proximal promoter region of p21. This
(Contente et al., 2002). Another recently described example is interaction effectively represses p21 induction by p53 and
the gene encoding the pro-apoptotic phosphatase PAC1, which other activators (Herold et al., 2002; Seoane et al., 2002).
is induced through binding of p53 to a novel palindromic Intriguingly, this repression appears to be specific for p21,
binding site (Yin et al., 2003). This might represent a new because other p53-target genes, such as p53 upregulated
mechanism for transcriptional regulation of apoptotic genes by modulator of apoptosis (PUMA) and PIG3, are induced. This
p53, which differs from that already described (see below). block in p21 induction shifts the balance away from growth
arrest towards apoptosis (Seoane et al., 2002). It should be
noted, however, that arrested cells are not necessarily protected
Redox determination of p53 gene regulation from apoptosis. For example, normal thymocytes and mature
The nucleotide sequence of the binding site for p53 within the lymphocytes undergo p53-mediated apoptosis under certain
promoters of its target genes is a critical determinant in the stress conditions (Strasser et al., 1994). Interaction of p53 with
response to stress (UV light or γ-irradiation exposure). In several other proteins specifically enhances the induction of
response to DNA damage, the binding affinity of p53 for the apoptotic target genes. The apoptosis stimulating proteins of
promoter of the cell-cycle-regulating gene p21WAF/CIP1 (p21) p53 (ASPP), for example, increases the DNA binding and
is unchanged, whereas binding to the promoter of the DNA- transactivation activity of p53 on the promoters of apoptotic
repair-associated gene Gadd45 is reduced. This is due, genes (e.g. Bax and PIG3), while failing to promote binding to
primarily, to oxidation of Cys277, residing within human p53, the p21 promoter by a mechanism that remains to be defined
which contacts the third base (the first pyrimidine residue) in (Samuels-Lev et al., 2001).
the p53-binding consensus pentamer A/TGPyPyPy: where the A novel insight into the interplay between p53 and its family
p53-binding element of p21 is 5′-GAACATGTCCcAACA- members, p63 and p73, in the induction of apoptosis has been
TGTTg-3′ and that of GADD45 is 5′-GAACATGTCTAAG- recently revealed by Flores et al. (Flores et al., 2002). Their
CATGCTg-3′ (and where the critical residues that determine study of the effect of p63 and p73 on p53 transcriptional
the binding to Cys277 are indicated in red, and consensus- activity, using a selection of knockout mouse embryo
fitting bases are in uppercase). Although the mechanism of p53 fibroblasts (MEFs), defined two distinct classes of target gene.
Cys277 oxidation is unclear, it may be associated with the Whereas p53 alone is sufficient for the induction of p21 and
production of oxygen radicals that are induced in response to Mdm2, the induction of the apoptotic genes PERP, Bax and
exposure to high-dose UV light (Buzek et al., 2002). Noxa requires p53 together with p63 and p73. This finding
Only under reducing conditions is the affinity of p53 for the demonstrates an essential role for both p63 and p73 in the
Gadd45 promoter increased, which suggests that the reduction efficient induction of apoptotic target genes by p53. The
of Cys277 is necessary to enable binding of p53 to C-rich mechanism of this cooperation is currently unknown, but it
binding sequences, such as that of Gadd45. Intriguingly, Seo may involve an enhanced binding to and/or stabilization of the
et al. found that reduction of residues Cys275 and Cys277 by transcription complex on the promoters of p53 apoptotic target
selenomethionine (the major dietary source of selenium) genes by the cooperative action of all three members (Urist and
caused p53 to recruit the p53-binding redox factor Ref1 and Prives, 2002). In addition to the contribution of p63 and p73
activate DNA-repair machinery through the induction of to the apoptotic function of p53, they play an important role in
Gadd45, without affecting cell growth (Seo et al., 2002). Thus, the precise control of cell death during normal mouse
the redox state of p53 Cys277 appears to serve as a switch for development. p73 also plays a role in the induction of cell death
activating the DNA repair machinery. This selective activation in response to DNA damage, a process involving cooperation
of p53-dependent DNA repair activity has been proposed as a between the Abl tyrosine kinase and p73 (reviewed by Shaul,
novel approach to cancer prevention (Gudkov, 2002). 2000).

p53 co-activators p53-mediated apoptosis


The interaction between p53 and transcriptional co-activators Exacting discrimination between p53 arrest and apoptotic
also influences its affinity for promoters. It is therefore functions has been critical to the identification of the
plausible that the specific co-factors expressed in a particular importance of the latter in tumor suppression. A strong link
cellular context determine the repertoire of p53-target genes between the apoptotic function of p53 and tumor suppression
induced, and consequently whether the cell undergoes growth has been demonstrated using transgenic mice bearing an SV40
arrest or apoptosis, or even a particular apoptotic pathway large T antigen (LT) mutant, which inhibited pRb function
(Fig. 1), may be subject to the availability of co-activators without directly compromising p53 activity. p53-mediated
(Rozenfeld-Granot et al., 2002). growth arrest is however impaired in these mice owing to pRb
The p53 network 4079
loss of function, but the apoptotic activity is functional. These receptor (TNF-R) family and, through the formation of the
mice develop choroid plexus tumors, but at a slow rate owing death-inducing-signaling-complex (DISC) (Ashkenazi and
to continuous p53-dependent apoptosis. Elimination of p53 Dixit, 1998), leads to a cascade of activation of caspases,
from these mice, by crossbreeding with p53-null mice, resulted including caspase-8 and caspase-3, which in turn induce
in aggressive tumor development. This finding suggested that apoptosis. The intrinsic pathway is triggered in response
tumor suppression is primarily due to p53-mediated apoptosis to DNA damage and is associated with mitochondrial
(reviewed by Vogt Sionov and Haupt, 1999). The most depolarization and release of cytochrome c from the
compelling insight into this fundamental question came from mitochondrial intermembrane space into the cytoplasm.
a recent study using the Eµ-myc-mediated lymphoma mouse Cytochrome c, apoptotic protease-activating factor 1 (APAF-
model. The apoptotic pathway of the lymphoma cells was 1) and procaspase-9 then form a complex termed the
blocked either by retroviral expression of bcl-2 or a dominant apoptosome, in which caspase-9 is activated and promotes
negative caspase-9. The effect of this block on the growth of activation of caspase-3, caspase-6 and caspase-7 (reviewed by
these lymphomas was then tested in recipient mice. In the Nicholson and Thornberry, 2003). Recent studies, however,
apoptosis-impaired cells there was no selection for p53 link the extrinsic and intrinsic pathways, lending support to the
mutations, in contrast to cells that had intact apoptotic idea of converging rather than distinct pathways (Gross et al.,
pathways. Remarkably, in the apoptosis-impaired lymphoma 1999; Li et al., 1998).
cells expressing functional p53, the integrity of the genome and
the cell cycle checkpoints were maintained. Taken together
these studies support the notion that apoptosis is the critical The extrinsic pathway
function of p53 in tumor suppression. p53 can activate the extrinsic apoptotic pathway through the
How p53 mediates apoptosis has been a matter of intensive induction of genes encoding three transmembranes proteins:
study since this was first demonstrated (Yonish-Rouach et al., Fas, DR5 and PERP. The cell-surface receptor Fas (CD95/Apo-
1991). Numerous publications have recently described the 1), a member of the TNF-R family of receptors, is a key
importance of p53 transcriptional regulation of components of component of the extrinsic death pathway (Nagata and
both the extrinsic and intrinsic pathways. However, few target Golstein, 1995). Fas is activated by binding of its ligand, FasL,
gene products have been unequivocally established to be which is expressed predominantly by T cells (Muzio, 1998).
essential to p53-dependent apoptosis induction; we discuss the p53 induces Fas mRNA expression by binding to elements
supporting evidence below. p53 is also able to promote found in the promoter and first intron of the Fas gene (Muller
apoptosis through transcription-independent apoptotic et al., 1998). This induction occurs in response to γ-irradiation,
mechanisms. Under certain conditions, p53 induces apoptosis and it appears to be strictly tissue specific (Bouvard et al.,
in the absence of transcription or protein synthesis (e.g. Caelles 2000). p53-dependent Fas mRNA induction has been
et al., 1994). Moreover, transcriptionally inactive mutants of demonstrated in the spleen, thymus, kidney and lung, but not
p53 can induce apoptosis in certain cell types (Haupt et al., in the heart and liver (Bouvard et al., 2000). However, at least
1995), and PIASγ (protein inhibitor of activated STAT), which in lymphocytes, Fas appears to be dispensable for p53-
blocks binding of p53 to DNA, does not inhibit p53-mediated dependent apoptosis (Fuchs et al., 1997; O’Connor et al.,
apoptosis (Nelson et al., 2001). In general, the transcription- 2000). The importance of Fas as a p53 target in other cell types
independent apoptotic activities of p53 have been remains to be elucidated.
demonstrated in transformed cells rather than in normal cells In addition to stimulating Fas transcription, overexpressed
(e.g. lymphocytes or fibroblasts). Presumably, these activities p53 may enhance levels of Fas at the cell surface by promoting
of p53 require cooperation with other apoptotic factors – for trafficking of the Fas receptor from the Golgi (Bennett et al.,
instance E2F-1 (a transcription factor in the retinoblastoma 1998). This may allow p53 to rapidly sensitize cells to Fas-
protein pathway) (reviewed by Vogt Sionov and Haupt, 1999). induced apoptosis before the transcription-dependent effect
Experimental cell transformation may mimic various stages of operates. How p53 promotes Fas trafficking is not understood.
tumor development, where the apoptotic function of p53 is The second member of this receptor family that is induced
being activated and becomes critical for the suppression of by p53 is DR5/KILLER, the death-domain-containing receptor
tumor progression. These apoptotic activities of p53 may not for TNF-related apoptosis-inducing ligand (TRAIL). DR5 is
be sufficient to induce apoptosis in non-transformed cells, such induced by p53 in response to DNA damage (Wu et al., 1997)
as normal thymocytes. Whereas the transcription-dependent and in turn promotes cell death through caspase-8 (reviewed
and -independent apoptotic functions of p53 are often by Ashkenazi and Dixit, 1998). DR5 induction is cell type
described separately, they appear to complement each other. specific. Whole body γ-irradiation induces DR5 expression in
We therefore discuss their contributions together in the context the spleen, small intestine and thymus (Burns et al., 2001),
of the extrinsic and intrinsic apoptotic pathways. which is consistent with DR5 participating in the p53-mediated
response to DNA damage in these tissues. Strikingly, in MEFs
exposed to DNA damage (by doxorubicin), similar levels of
Extrinsic and intrinsic apoptotic pathways DR5 were identified in cells undergoing G1 arrest and
p53 is implicated in the induction of what had until recently apoptosis (Attardi et al., 2000). Thus, the contribution of DR5
been understood to be two distinct apoptotic signaling to these different p53-determined cell fates remains to be
pathways that lead to the activation of the aspartate-specific clarified.
cysteine proteases (caspases) that mediate apoptosis (Fig. 1). Another apoptotic gene, PERP, is induced in MEFs in
The extrinsic pathway involves engagement of particular response to DNA-damage in cells transduced with either E2F-
‘death’ receptors that belong to the tumor necrosis factor 1 or with the adenoviral E1A protein, which targets pRb,
4080 Journal of Cell Science 116 (20)

Extrinsic
rinsic FAS-L
path
hway
? FAS
FAS
FAS
t raffic
king
?
Golgi

Bid
Bi d

Cyt c

'Apoptosome' Apaf-1 Mitochon


ndr
dria
ria ax

Caspase-9 ntrriinsic
pat
path
pathway
Caspase-3

Caspase-6
e

Caspase-7
e

Apoptosis
Fig. 1. A model for p53-mediated apoptosis. This model depicts the involvement of p53 in the extrinsic and intrinsic apoptotic pathways. p53
target genes are shown in red. The convergence of the two pathways through Bid is shown.

thereby releasing active E2F-1. In this context, PERP probably members, is the minimum domain required for the pro-
cooperates with E2F-1 to induce apoptosis. PERP is a putative apoptotic function (Kelekar and Thompson, 1998; Yu et al.,
tetraspan transmembrane protein that represents a new member 2001). The Bcl-2 family is divisible into three classes: pro-
of the PMP-22/gas family of proteins implicated in cell growth survival proteins, whose members are most structurally similar
regulation. The kinetics of PERP induction in response to DNA to Bcl-2, such as Bcl-XL; pro-apoptotic proteins, Bax and Bak,
damage and the presence of a p53-responsive element in the which are structurally similar to Bcl-2 and Bcl-XL and
PERP promoter support the notion that it is a direct p53 target. antagonize their pro-survival functions; and the pro-apoptotic
A role for PERP in apoptosis is suggested by the significantly ‘BH3-only’ proteins (Bouillet and Strasser, 2002). Intriguingly,
higher levels of PERP mRNA in cells undergoing apoptosis a key subset of the Bcl-2 family genes are p53 targets,
than in arresting cells. However, the mechanism by which including Bax, Noxa, PUMA and the most recently identified,
PERP contributes to p53-mediated apoptosis is yet to be Bid.
defined (Attardi et al., 2000). Bax was the first member of this group shown to be induced
by p53, but p53-responsive elements have only recently been
unequivocally identified in the Bax gene (Thornborrow et al.,
The intrinsic pathway 2002). In response to stress activation, Bax forms a homodimer
The intrinsic apoptotic pathway is dominated by the Bcl-2 and releases cytochrome c from the mitochondria (Skulachev,
family of proteins, which governs the release of cytochrome c 1998), which results in caspase-9 activation (reviewed by
from the mitochondria (Cory and Adams, 2002; Kuwana et Adams and Cory, 1998). The requirement for Bax in p53-
al., 2002). The Bcl-2 family comprises anti-apoptotic (pro- mediated apoptosis appears to be cell-type dependent. Bax is
survival) and pro-apoptotic members. Family members are required for the apoptotic response of the developing nervous
classified on the basis of structural similarity to the Bcl-2 system to γ-irradiation (Chong et al., 2000) and contributes to
homology (BH) domains (BH1, BH2, BH3 and BH4), and a chemotherapy-induced killing of E1A-expressing fibroblasts
transmembrane domain. The BH3 domain, which is present in (McCurrach et al., 1997).
all members and is essential for heterodimerization among In contrast, equivalent levels of Bax induced in MEFs
The p53 network 4081
undergoing either arrest or apoptosis had been understood to contribute to p53-mediated apoptosis, but perhaps is not
indicate that Bax does not dictate cellular fate in these cells essential for it to occur, at least in thymocytes.
(Attardi et al., 2000). In addition, in colonic epithelia
undergoing apoptosis in response to γ-irradiation, Bax did not
appear to be essential (Pritchard et al., 1999). Caspase activation
A fascinating explanation for the apparent enigmatic role of Caspase-9 and caspase-2 respond to changes in mitochondrial
Bax in apoptosis induction has recently been offered in the potential, whereas caspase-8 and caspase-10 sense activation
context of PUMA. The PUMA gene is also directly induced by of death receptors. These initiator caspases cleave the pro-
p53 in response to DNA damage, through p53-responsive enzyme forms of the effector caspases, caspase-3, caspase-6
elements within the first intron of PUMA. In humans, PUMA and caspase-7, allowing digestion of essential targets that affect
encodes two BH3-domain-containing proteins, PUMA-α and cell viability (Fig. 1) (MacLachlan and El-Deiry, 2002).
PUMA-β (Nakano and Vousden, 2001; Yu et al., 2001). A vital Intriguingly, p53 boosts the activation of the caspase
balance between PUMA and p21 has been identified to cascade by both transcription-dependent and -independent
determine the onset of arrest, or death, in response to mechanisms. In response to γ-irradiation of nucleus-depleted
exogenous p53 expression and also hypoxia in human S100 cell-free extracts, p53 can activate caspase-8 (Ding et al.,
colorectal cancer cells. Growth arrest through activation of p21 1998). Depletion or inactivation of caspase-8 in cell-free
is the normal response to p53 expression in these cells. If p21 extracts completely prevents this effect and significantly
is disrupted the cells die through apoptosis; if, however, PUMA attenuates overall apoptosis induced by wild-type p53.
is disrupted, apoptosis is prevented. Bax is absolutely required However, etoposide- and UV-mediated death of fibroblasts
for PUMA-mediated apoptosis. PUMA expression promotes derived from caspase-8-deficient mice is not impaired
mitochondrial translocation and mulitmerization of Bax, (Varfolomeev et al., 1998). Thus, caspase-8 can contribute to,
culminating in apoptosis induction (Yu et al., 2003). Thus, although is not always essential for, DNA-damaged induced
although p53 can bind to the Bax promoter, the affinity is weak death.
in contrast to p21 and PUMA binding (Kaeser and Iggo, 2002). p53 stimulates caspase-6 through a more conventional
Bax thus participates in the death response as an indirect target mechanism. In response to DNA damage, p53 directly induces
of p53 through PUMA (Yu et al., 2003). caspase-6 expression through a response element within the
Another p53 target gene, Noxa, contains a single p53- third intron of the gene (MacLachlan and El-Deiry, 2002).
responsive element in its promoter and is induced in response Caspase-6 cleaves the nuclear envelope protein lamin A and
to X-ray irradiation (Oda et al., 2000). Noxa encodes a BH3- several transcription factors (Galande et al., 2001). Caspase-6
only protein and hence is likely to contribute to p53-mediated plays an important role in p53-induced neuronal cell death and
apoptosis in a similar manner to PUMA and Bax, although this is the major protein involved in the cleavage of the amyloid
is yet to be demonstrated. Thus, it appears that, in response to precursor protein (LeBlanc et al., 1999).
DNA damage, p53 activates the intrinsic mitochondrial
apoptotic pathway by inducing the expression of at least three
Bcl-2 pro-apoptotic family members, shifting the balance p53 localization to the mitochondria
towards pro-apoptotic effects. p53 also participates in apoptosis induction by acting directly
at mitochondria. Localization of p53 to the mitochondria
occurs in response to apoptotic signals and precedes
Apoptosome activation by p53 cytochrome c release and procaspase-3 activation. Importantly,
The formation of the apoptosome requires the release of redirecting p53 to mitochondria by using mitochondrial-import
cytochrome c and APAF-1 from mitochondria and their leader peptides is sufficient to induce apoptosis in p53-deficient
formation of a complex with pro-caspase-9 (Adams and Cory, Saos-2 cells (Marchenko et al., 2000). Recently Mihara et al.
2002). p53 promotes cytochrome c release through the also extended this finding to show that p53 promotes
induction of target genes encoding BH3-only proteins. permeabilization of the outer mitochondrial membrane by
Importantly, p53 also induces APAF-1 expression through a forming complexes with the protective Bcl-XL and Bcl-2
response element within the APAF-1 promoter (Kannan et al., proteins. Interestingly, p53 binds through its DNA-binding
2001; Moroni et al., 2001; Robles et al., 2001; Rozenfeld- domain to Bcl-XL. Tumor-derived transactivation-deficient
Granot et al., 2002). This induction by p53 is boosted by E2F- mutants of p53 cannot interact with Bcl-XL and hence do not
1, which induces APAF-1 expression, and activates p53 in promote mitochondrial apoptotic events, even though they
an ARF-dependent manner (Moroni et al., 2001). APAF-1, localize to the mitochondria (Mihara et al., 2003). Separating
is required for stress-induced p53-dependent apoptosis of these two activities of p53 may shed light on the biological
fibroblasts and also for the induction of apoptosis by Myc, in relevance of p53 localization to the mitochondria. Since p53
which caspase-9 is an essential downstream component can mediate apoptosis without its DNA-binding domain (Haupt
(Soengas et al., 1999). In another study the response to IR of et al., 1995) it is likely that the mitochondrial localization of
thymocytes from Apaf-1/caspase-9 null mice was compared p53 is not the only transcription-independent mechanism by
with that of normal mice. This comparison revealed an which p53 promotes apoptosis.
impaired response, but neither protection from apoptosis nor
normal sensitivity to IR-induced death (Marsden et al., 2002).
This apparent difference may represent a different role for the BID: a link between the extrinsic and intrinsic
apoptosome in Myc-expressing fibroblasts versus normal apoptotic pathways
thymocytes. It may also suggest that the apoptosome can The pro-apoptotic Bid is distinguished by its unique ability to
4082 Journal of Cell Science 116 (20)
Stress signals Growth/survival factors

Fig. 2. A model for the p110 p85


85 p110 p85
regulation of p53 by the
AKT pathway under PI3K
PI3K PI3K
growth/survival conditions
and under stress signals. AKT
The negative regulation of AKT
p53 by AKT is induced in
AKT degrad
A
AK dation
response to survival signals
from Mdm2. The activation Mdm2
of this pathway leads to the Mdm2
inhibition and destruction PTEN Cytoplasm
of p53. Under stress
conditions this pathways is
Mdm2
blocked through the
cleavage and degradation of
AKT, and the inhibition of
PI3K through PTEN. Both
of these activities are Mdm2
p53 p53 p53 degradation
induced by p53. In this
model survival is achieved
by inhibition of p53 by p53 active p53 inactive
AKT, whereas apoptosis is
achieved by counteracting Growth inhibition
AKT by p53. p53 target N cle s
Nucleus
genes are shown in red.
Green arrows represent
activation, whereas red
arrows represent inhibition.

connect activation of the extrinsic death receptor pathway to (PI3K) activating signaling pathways that promote cell
activation of the mitochondrial-disruption processes associated proliferation and viability (Fig. 2). PI3K comprises a p85
with the intrinsic pathway. Activation of Bid involves cleavage regulatory subunit, which interacts with phosphorylated
of cytoplasmic Bid by caspase-8 to expose a new N-terminal receptor tyrosine kinases, and the 110 kDa subunit, which
glycine residue, which undergoes post-translational localizes to the membrane upon receptor binding. In response
myristoylation. Myristoylated Bid translocates to the to a change in redox state caused by H2O2-induced oxidative
mitochondria, inserts into the membrane and activates BAX stress, p85 is upregulated by p53. p85 is involved in the p53-
and BAK to initiate mitochondrial events leading to dependent apoptotic response to H2O2 in MEFs, but its precise
apoptosome formation. The Bid gene is transcriptionally role in cell death is unclear. PI3K activates AKT, a
regulated by p53 in response to γ-irradiation through response serine/threonine kinase, through phosphorylation on Ser473 by
elements in the first intron of the human gene or in the the 3′-phosphoinositide-dependent kinase PDK1 (Lawlor and
promoter of the mouse gene. Bid mRNA increases in a p53- Alessi, 2001). In turn, AKT phosphorylates a range of targets
dependent manner in the splenic red pulp and the colonic that function to promote cell survival, including the major
epithelium; however, a correlation with an increase in Bid inhibitor of p53, Mdm2 (reviewed by Mayo and Donner, 2002).
protein levels needs to be shown. Cellular chemosensitivity to This phosphorylation enhances the nuclear accumulation of
the DNA-damaging agents adriamycin and 5-fluorouracil Mdm2, augments Mdm2 interaction with p300, and reduces
appears to be critically dependent on the presence of wild-type the affinity of Mdm2 for p19ARF (reviewed by Testa and
p53 and Bid, Bid-null cells being resistant to the effects of these Bellacosa, 2001). Consequently, AKT augments the inhibition
drugs (Sax et al., 2002). p53 therefore appears to promote the and destabilization of p53 by Mdm2 (Fig. 2). Interestingly,
convergence of the intrinsic and extrinsic pathways through stress-induced activation of p53 counteracts the inhibitory
Bid regulation. effects of this survival pathway by multiple mechanisms (Fig.
2). First, p53 promotes caspase-mediated cleavage and
subsequent degradation of the AKT protein itself (Gottlieb et
p53-mediated abrogation of survival signals: the al., 2002). Second, p53 induces the expression of the PTEN
AKT pathway tumor suppressor gene, which encodes a phosphatase that de-
Binding of mitogens and cytokines to cell surface receptors phosphorylates PI3K, thereby impairing AKT activation
including the insulin receptor, the epidermal growth factor (reviewed by Mayo and Donner, 2002). Third, p53 induces
receptor (EGFR) and the platelet-derived growth factor expression of cyclin G, which in turn recruits the phosphatase
receptor (PDGFR), and the actions of oncogenes such as Ras PP2AB’ to the Mdm2-p53 complex, where it de-
and Her2/Neu, is transduced by phosphoinositide 3-kinase phosphorylates Mdm2 at the AKT phosphorylation sites. These
The p53 network 4083
feedback loops determine the survival versus apoptotic through the activation of specific p53-target genes. In addition,
outcome in the interplay between p53 and the AKT survival p53 is able to activate apoptotic pathways by transcription-
pathway (Fig. 2) (reviewed by Oren et al., 2002). This fine independent mechanisms (including direct shuttling of p53 to
balance is often interrupted in cancer, either by mutations in the mitochondrial membrane), more of which are likely to be
PTEN or amplification of Mdm2 (Mayo and Donner, 2002). unraveled in the future. Why is this complex apoptotic network
required? One possible reason may be to ensure a rapid
response. Another is that specific sets of target genes might be
p53-mediated cancer therapy activated under a given set of conditions, in a stage-, tissue-
Stimulation of disabled p53 pathways has been suggested as a and stimulus-specific manner. Alternatively, active p53 may
potential mode of therapy for cancer: potential approaches induce the same set of target genes under different conditions,
include introducing wild-type p53 genetically, empowering the specificity being determined by other cellular factors.
aberrant p53 molecules to perform wild-type functions, or Currently there are examples to support each of these options.
intervening to activate directly targets in the p53 apoptotic Defining the effect of these variables on p53 transcriptional
pathways. Gene therapy based on the introduction of wild-type activity using genome-wide expression analysis may help to
p53 (reviewed by Wen et al., 2003) and elimination of mutant- answer some of these fundamental questions. Such analyses
p53-expressing cells (reviewed by Post, 2002) is undergoing are likely to shed new light on the determinants of the cellular
clinical trials. Restoration of wild-type conformation to decision between growth arrest and apoptosis.
structurally contorted p53 DNA-binding mutants has been
demonstrated, using peptide constructs and small molecular We are grateful to Mati Goldberg for drawing the illustrations.
weight synthetic molecules (reviewed by Bullock and Fersht, Owing to space limitations many original important studies have not
2001). Synthetic peptides derived from the C-terminus of p53 been cited directly but rather through recent reviews. The work in
Y.H.’s laboratory is supported by the Research Career Development
can induce p53-dependent apoptosis in tumor cells and restore Award from the Israel Cancer Research Fund, the Israel Science
the specific DNA-binding and transcription functions to mutant Foundation, the Ministry of Health, a grant from the Ministry of
p53 in vitro (Abarzua et al., 1996; Selivanova et al., 1997; Science Culture and Sport Israel and the DKFZ, the Israel Cancer
Selivanova et al., 1999). In vivo activity of these peptides has Association through the ‘Ber-Lehmsdorf’ memorial fund in memory
been associated with an increase in the levels of the Fas of the late Prof. Nathan Training, and in part by research grant 1-
receptor on the cell surface, through a p53-dependent FY01-177 from the March of Dimes Birth Defects Foundation.
mechanism that is independent of transcription (Kim et al.,
1999). Other small synthetic peptides derived from a p53-
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