1 Department of Pharmacy, The Hebrew University Hadassah Medical School, Jerusalem 91120, Israel
2 Lautenberg Center for General and Tumor Immunology, The Hebrew University Hadassah Medical School, Jerusalem 91120, Israel
* Author for correspondence (e-mail: haupt{at}md.huji.ac.il)
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Summary |
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Key words: p53, Apoptosis, Caspase, Mitochondria, Transcriptional activation
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Introduction |
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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 development. Indeed, approximately 50% of human cancers bear p53 gene mutations; in the majority of the remaining cancer cases, p53 activity is compromised by alternative mechanisms (Vogelstein et al., 2000). These involve elevation in the expression levels of p53 inhibitors, such as Mdm2 or the E6 protein of HPV, or silencing of key p53 co-activators, such as ARF (Vogelstein et al., 2000
; Vogt Sionov et al., 2001
).
Under normal conditions p53 is a short-lived protein. The p53 inhibitor Mdm2 (Hdm2 in humans) is largely responsible for keeping p53 in this state. Mdm2 inhibits the transcriptional activity of p53 and, more importantly, promotes its degradation by the proteasome. However, the status of p53 is drastically altered when cells are exposed to stress, including DNA damage, untimely expression of oncogenes, hypoxia and nucleotide depletion (reviewed by Giaccia and Kastan, 1998). p53 activation involves stabilization of the protein, and enhancement of its DNA binding and transcriptional activity. These changes in p53 are mediated by extensive post-translational modifications of p53 and protein-protein interactions with cooperating factors. Ultimately, the activation of p53 leads to cell growth arrest, senescence or apoptosis, the choice of which depends on the summation of the incoming signals and the cellular context (see below). Because the apoptotic function of p53 is critical for tumor suppression, reconstitution of inactive p53-dependent apoptotic pathways is an attractive approach currently being explored for anti-cancer treatment. Here, we review recent developments in our understanding of p53-mediated apoptosis. References to relevant exhaustive reviews on this subject are made in the appropriate sections.
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Growth inhibition by p53: cell cycle arrest or apoptosis? |
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Redox determination of p53 gene regulation |
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Only under reducing conditions is the affinity of p53 for the Gadd45 promoter increased, which suggests that the reduction of Cys277 is necessary to enable binding of p53 to C-rich binding sequences, such as that of Gadd45. Intriguingly, Seo et al. found that reduction of residues Cys275 and Cys277 by selenomethionine (the major dietary source of selenium) caused p53 to recruit the p53-binding redox factor Ref1 and activate DNA-repair machinery through the induction of Gadd45, without affecting cell growth (Seo et al., 2002). Thus, the redox state of p53 Cys277 appears to serve as a switch for activating the DNA repair machinery. This selective activation of p53-dependent DNA repair activity has been proposed as a novel approach to cancer prevention (Gudkov, 2002
).
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p53 co-activators |
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The Myc protein has been implicated as an important determinant of the choice between p53-induced growth arrest or apoptosis. Myc inhibits growth arrest in response to UV light, -irradiation and DNA damage inflicted by reactive oxygen species (Sheen and Dickson, 2002
; Vafa et al., 2002
). In the absence of Myc, cells that are exposed to UV light arrest in a p53- and Miz-1 (DNA-binding Myc-interacting zinc-finger 1)-dependent manner through activation of p21. However, when Myc is present, exposure to UV triggers its recruitment by Miz-1 to the proximal promoter region of p21. This interaction effectively represses p21 induction by p53 and other activators (Herold et al., 2002
; Seoane et al., 2002
). Intriguingly, this repression appears to be specific for p21, because other p53-target genes, such as p53 upregulated modulator of apoptosis (PUMA) and PIG3, are induced. This 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 from apoptosis. For example, normal thymocytes and mature lymphocytes undergo p53-mediated apoptosis under certain stress conditions (Strasser et al., 1994
). Interaction of p53 with several other proteins specifically enhances the induction of apoptotic target genes. The apoptosis stimulating proteins of p53 (ASPP), for example, increases the DNA binding and transactivation activity of p53 on the promoters of apoptotic genes (e.g. Bax and PIG3), while failing to promote binding to the p21 promoter by a mechanism that remains to be defined (Samuels-Lev et al., 2001
).
A novel insight into the interplay between p53 and its family members, p63 and p73, in the induction of apoptosis has been recently revealed by Flores et al. (Flores et al., 2002). Their study of the effect of p63 and p73 on p53 transcriptional activity, using a selection of knockout mouse embryo fibroblasts (MEFs), defined two distinct classes of target gene. Whereas p53 alone is sufficient for the induction of p21 and Mdm2, the induction of the apoptotic genes PERP, Bax and Noxa requires p53 together with p63 and p73. This finding demonstrates an essential role for both p63 and p73 in the efficient induction of apoptotic target genes by p53. The mechanism of this cooperation is currently unknown, but it may involve an enhanced binding to and/or stabilization of the transcription complex on the promoters of p53 apoptotic target genes by the cooperative action of all three members (Urist and Prives, 2002
). In addition to the contribution of p63 and p73 to the apoptotic function of p53, they play an important role in the precise control of cell death during normal mouse development. p73 also plays a role in the induction of cell death in response to DNA damage, a process involving cooperation between the Abl tyrosine kinase and p73 (reviewed by Shaul, 2000
).
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p53-mediated apoptosis |
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How p53 mediates apoptosis has been a matter of intensive study since this was first demonstrated (Yonish-Rouach et al., 1991). Numerous publications have recently described the importance of p53 transcriptional regulation of components of both the extrinsic and intrinsic pathways. However, few target gene products have been unequivocally established to be essential to p53-dependent apoptosis induction; we discuss the supporting evidence below. p53 is also able to promote apoptosis through transcription-independent apoptotic mechanisms. Under certain conditions, p53 induces apoptosis in the absence of transcription or protein synthesis (e.g. Caelles et al., 1994
). Moreover, transcriptionally inactive mutants of p53 can induce apoptosis in certain cell types (Haupt et al., 1995
), and PIAS
(protein inhibitor of activated STAT), which blocks binding of p53 to DNA, does not inhibit p53-mediated apoptosis (Nelson et al., 2001
). In general, the transcription-independent apoptotic activities of p53 have been demonstrated in transformed cells rather than in normal cells (e.g. lymphocytes or fibroblasts). Presumably, these activities of p53 require cooperation with other apoptotic factors - for instance E2F-1 (a transcription factor in the retinoblastoma protein pathway) (reviewed by Vogt Sionov and Haupt, 1999
). Experimental cell transformation may mimic various stages of tumor development, where the apoptotic function of p53 is being activated and becomes critical for the suppression of tumor progression. These apoptotic activities of p53 may not be sufficient to induce apoptosis in non-transformed cells, such as normal thymocytes. Whereas the transcription-dependent and -independent apoptotic functions of p53 are often described separately, they appear to complement each other. We therefore discuss their contributions together in the context of the extrinsic and intrinsic apoptotic pathways.
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Extrinsic and intrinsic apoptotic pathways |
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The extrinsic pathway |
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In addition to stimulating Fas transcription, overexpressed p53 may enhance levels of Fas at the cell surface by promoting trafficking of the Fas receptor from the Golgi (Bennett et al., 1998). This may allow p53 to rapidly sensitize cells to Fas-induced apoptosis before the transcription-dependent effect operates. How p53 promotes Fas trafficking is not understood.
The second member of this receptor family that is induced by p53 is DR5/KILLER, the death-domain-containing receptor for TNF-related apoptosis-inducing ligand (TRAIL). DR5 is induced by p53 in response to DNA damage (Wu et al., 1997) and in turn promotes cell death through caspase-8 (reviewed by Ashkenazi and Dixit, 1998
). DR5 induction is cell type specific. Whole body
-irradiation induces DR5 expression in the spleen, small intestine and thymus (Burns et al., 2001
), 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 DR5 were identified in cells undergoing G1 arrest and apoptosis (Attardi et al., 2000
). Thus, the contribution of DR5 to these different p53-determined cell fates remains to be clarified.
Another apoptotic gene, PERP, is induced in MEFs in response to DNA-damage in cells transduced with either E2F-1 or with the adenoviral E1A protein, which targets pRb, thereby releasing active E2F-1. In this context, PERP probably cooperates with E2F-1 to induce apoptosis. PERP is a putative tetraspan transmembrane protein that represents a new member of the PMP-22/gas family of proteins implicated in cell growth regulation. The kinetics of PERP induction in response to DNA damage and the presence of a p53-responsive element in the PERP promoter support the notion that it is a direct p53 target. A role for PERP in apoptosis is suggested by the significantly higher levels of PERP mRNA in cells undergoing apoptosis than in arresting cells. However, the mechanism by which PERP contributes to p53-mediated apoptosis is yet to be defined (Attardi et al., 2000).
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The intrinsic pathway |
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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., 2002). In response to stress activation, Bax forms a homodimer and releases cytochrome c from the mitochondria (Skulachev, 1998
), which results in caspase-9 activation (reviewed by Adams and Cory, 1998
). The requirement for Bax in p53-mediated apoptosis appears to be cell-type dependent. Bax is required for the apoptotic response of the developing nervous system to
-irradiation (Chong et al., 2000
) and contributes to chemotherapy-induced killing of E1A-expressing fibroblasts (McCurrach et al., 1997
).
In contrast, equivalent levels of Bax induced in MEFs undergoing either arrest or apoptosis had been understood to indicate that Bax does not dictate cellular fate in these cells (Attardi et al., 2000). In addition, in colonic epithelia undergoing apoptosis in response to
-irradiation, Bax did not appear to be essential (Pritchard et al., 1999
).
A fascinating explanation for the apparent enigmatic role of Bax in apoptosis induction has recently been offered in the context of PUMA. The PUMA gene is also directly induced by p53 in response to DNA damage, through p53-responsive elements within the first intron of PUMA. In humans, PUMA encodes two BH3-domain-containing proteins, PUMA- and PUMA-ß (Nakano and Vousden, 2001
; Yu et al., 2001
). A vital balance between PUMA and p21 has been identified to determine the onset of arrest, or death, in response to exogenous p53 expression and also hypoxia in human colorectal cancer cells. Growth arrest through activation of p21 is the normal response to p53 expression in these cells. If p21 is disrupted the cells die through apoptosis; if, however, PUMA is disrupted, apoptosis is prevented. Bax is absolutely required for PUMA-mediated apoptosis. PUMA expression promotes mitochondrial translocation and mulitmerization of Bax, culminating in apoptosis induction (Yu et al., 2003
). Thus, although p53 can bind to the Bax promoter, the affinity is weak in contrast to p21 and PUMA binding (Kaeser and Iggo, 2002
). Bax thus participates in the death response as an indirect target of p53 through PUMA (Yu et al., 2003
).
Another p53 target gene, Noxa, contains a single p53-responsive element in its promoter and is induced in response to X-ray irradiation (Oda et al., 2000). Noxa encodes a BH3-only protein and hence is likely to contribute to p53-mediated apoptosis in a similar manner to PUMA and Bax, although this is yet to be demonstrated. Thus, it appears that, in response to 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 towards pro-apoptotic effects.
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Apoptosome activation by p53 |
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Caspase activation
Caspase-9 and caspase-2 respond to changes in mitochondrial potential, whereas caspase-8 and caspase-10 sense activation of death receptors. These initiator caspases cleave the pro-enzyme forms of the effector caspases, caspase-3, caspase-6 and caspase-7, allowing digestion of essential targets that affect cell viability (Fig. 1) (MacLachlan and El-Deiry, 2002). Intriguingly, p53 boosts the activation of the caspase cascade by both transcription-dependent and -independent mechanisms. In response to
-irradiation of nucleus-depleted S100 cell-free extracts, p53 can activate caspase-8 (Ding et al., 1998
). Depletion or inactivation of caspase-8 in cell-free extracts completely prevents this effect and significantly attenuates overall apoptosis induced by wild-type p53. However, etoposide- and UV-mediated death of fibroblasts derived from caspase-8-deficient mice is not impaired (Varfolomeev et al., 1998
). Thus, caspase-8 can contribute to, although is not always essential for, DNA-damaged induced death.
p53 stimulates caspase-6 through a more conventional mechanism. In response to DNA damage, p53 directly induces caspase-6 expression through a response element within the third intron of the gene (MacLachlan and El-Deiry, 2002). Caspase-6 cleaves the nuclear envelope protein lamin A and several transcription factors (Galande et al., 2001
). Caspase-6 plays an important role in p53-induced neuronal cell death and is the major protein involved in the cleavage of the amyloid precursor protein (LeBlanc et al., 1999
).
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p53 localization to the mitochondria |
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BID: a link between the extrinsic and intrinsic apoptotic pathways |
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p53-mediated abrogation of survival signals: the AKT pathway |
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p53-mediated cancer therapy |
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Conclusion |
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Acknowledgments |
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