Apoptosis La Red de p53
Apoptosis La Red de p53
Apoptosis La Red de p53
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
Extrinsic
rinsic FAS-L
path
hway
? FAS
FAS
FAS
t raffic
king
?
Golgi
Bid
Bi d
Cyt c
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
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-
binding protein have been introduced to restore sequence- References
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