Regulation of p53 stability

Abstract

Leading the way in imposing a policy of zero tolerance of cellular abnormalities that might lead to tumor development is the p53 protein. The efficiency of p53 in preventing cell growth is a strong deterrent to malignant progression, but this activity must be kept tightly restrained to allow normal cell growth and development. Essential components of this regulation are the mechanisms by which the p53 protein is degraded, and efficient turnover of p53 in normal cells prevents the accumulation of the protein. Modulation of these degradation pathways in response to stress leads to the rapid stabilization and accumulation of p53, and activation of the p53 response. It is now becoming clear that the Mdm2 protein is central to the regulation of p53 stability and multiple pathways exist through which the activity of Mdm2 can be inhibited. Defects in the ability to stabilize p53 are likely to contribute to malignant development, and restoration of this activity represents an extremely attractive possibility for tumor therapy.

Introduction

The p53 protein is a potent inhibitor of cell growth, arresting the cell cycle at several points and, under some circumstances, activating the apoptotic machinery leading to cell death (Bates and Vousden, 1996). These multiple functions of p53 in preventing cell growth are of critical importance for tumor suppression, and loss of p53 greatly enhances the risk of the development of malignancies in mice and men (Evans and Lozano, 1997; Attardi and Jacks, 1999). Equally important, however, are the mechanisms that keep these activities of p53 under control during normal cell growth. Unlike some other members of the p53 family, p53 function is not absolutely necessary for normal cell growth and differentiation, although embryonic development can be impacted by loss of p53 (Choi and Donehower, 1999). Unwarranted activation of p53 function, on the other hand, is catastrophic to the developing embryo, and therefore mechanisms that exert extremely strict control over p53 are of paramount importance. Several levels of regulation of p53 have been described, including control of transcription and translation. The principal mechanism through which p53 activity is governed, however, is by controlling the stability of the p53 protein, and astonishing progress has been made in our understanding of these pathways over the past few years.

Regulation of p53 stability

In normal cells p53 is present at extremely low levels because the protein is very rapidly degraded following synthesis (Kubbutat and Vousden, 1998). Regulation of protein stability is a common mechanism by which the function of cell growth regulatory proteins is controlled and p53, like many other proteins, is targeted for degradation by the proteasome following ubiquitination. This form of proteolysis involves a system of enzymes that conjugate multiple ubiquitin chains to lysines in the targeted protein (Varshavsky, 1997). These polyubiquitinated proteins are then recognized and degraded by the proteasome. Attachment of ubiquitin to the proteins destined for degradation depends on three activities; E1, the ubiquitin-activating enzyme, E2, the ubiquitin-conjugating enzyme and E3, the ubiquitin-ligase. The ubiquitin-ligases comprise a large and diverse group of proteins, sometimes functioning in large multiprotein complexes, and these are the enzymes that are responsible for determining the substrate specificity of the ubiquitin pathway.

Mdm2 and the degradation of p53

One of the important components of the p53 degradation pathway is Mdm2, the product of a gene that is a target for transcriptional trans-activation by p53. As with other p53 targets, expression of Mdm2 is enhanced following activation of a p53 response, although unlike other p53 targets there is no evidence that Mdm2 mediates any of the downstream effects of p53, such as cell cycle arrest or apoptosis (Marston et al., 1994; Reinke and Lozano, 1997). The principal role of Mdm2 in the p53 pathway is to directly interact with the p53 protein and inhibit p53 activity. Mdm2 binds to the N-terminus of p53, within the trans-activation domain where p53, as a transcription factor, contacts other components of the basal transcriptional machinery. The binding of Mdm2 alone inhibits the normal function of this region of p53, reducing the ability of p53 to activate gene expression (Momand et al., 1992; Oliner et al., 1993). But this is not the only way in which Mdm2 controls p53, and numerous recent studies have shown that Mdm2 also participates in the degradation of p53 (Kubbutat and Vousden, 1998). The control that Mdm2 exerts over p53 is essential for normal development, since Mdm2 deficient mice show a very early embryonic lethality (Jones et al., 1995; Montes de Oca Luna et al., 1995). The observation that this lethality is entirely rescued by the simultaneous deletion of p53 strongly supports the model in which loss of Mdm2 leads to uncontrolled p53 activity. Further evidence for the importance of the Mdm2/p53 regulatory pathway is illustrated by tumor cells expressing transcriptionally inactive mutant forms of p53. In addition to failing to elicit a tumor suppressor response, these mutant p53s are also unable to activate expression of Mdm2, and as a result the mutant p53 proteins are unusually stable and accumulate to high levels in the tumor cells (Kubbutat and Vousden, 1998). Under conditions where Mdm2 is expressed, in a cell also containing wild type p53 for example, the tumor-derived p53 mutants are degraded as rapidly as the wild type protein (Midgley and Lane, 1997).

Functions of Mdm2

Mdm2 appears to play more than one role in targeting degradation of p53. Several studies have now shown that Mdm2 can function as an E3 ubiquitin-ligase and allow ubiquitination of p53 in vitro (Honda et al., 1997; Fang et al., unpublished observations). This activity of Mdm2 depends on both the p53-binding region at the N-terminus and the RING finger domain in the C-terminus of the Mdm2 protein and both these regions are essential for Mdm2 targeted degradation of p53 in cells (Kubbutat et al., 1999). In this respect, Mdm2 resembles several other recently described E3 ubiquitin-ligases, which also contain RING finger domains, reflecting their common function (Tyler and Willems, 1999). Interestingly, Mdm2 appears not only to target p53 for degradation but also has auto-ubiquitination activity and is therefore likely to regulate its own stability (Honda and Yasuda, 1999). Indeed, mutations in the RING finger which prevent ubiquitination and degradation of p53 result in an Mdm2 protein which is also unusually stable and expressed at high levels (Kubbutat et al., 1999).

The ability of Mdm2 to function as a ubiquitin-ligase for p53 clearly could contribute to the regulation of p53 stability, but there is another activity of Mdm2 that also plays a role in this process. The Mdm2 protein contains both nuclear import and nuclear export sequences, and mutations within the nuclear export sequences inhibit the ability of Mdm2 to promote the degradation of p53 (Roth et al., 1998). Specific inhibition of the nuclear export protein, CRM1, using the cytotoxic agent, leptomycin B, abrogates Mdm2's ability to degrade p53 (Freedman and Levine, 1998) and results in the accumulation of p53 and Mdm2 proteins as discrete nuclear aggregates (Lain et al., 1999). One explanation for these observations is that Mdm2 carries p53 from the nucleus into the cytoplasm, where degradation occurs through cytoplasmic proteasomes. However, p53 itself has a nuclear export sequence that functions in the absence of Mdm2 (Strommel et al., 1999), and the two proteins could shuttle independently of each other. Nevertheless, degradation of p53 by Mdm2 depends directly on the ability of Mdm2 to shuttle from the nucleus to cytoplasm (Tao and Levine, 1999), and another possibility is that shuttling of Mdm2 is necessary to activate the ubiquitin ligase function. In either case it is clear that regulation of subcellular localization is a potent mechanism to regulate p53 stability.

Despite the efficiency with which Mdm2 targets p53 for degradation, not all proteins that are complexed with Mdm2 are ubiquitinated and degraded. The p53 related protein p73, which also forms a complex with Mdm2, is not degraded as a consequence of this interaction (Balint and Vousden, 1999; Zeng et al., 1999) although, like p53, p73 levels are regulated through a proteasome dependent mechanism (Balint and Vousden, 1999). Mutational analysis has shown that the extreme C-terminus of p53 is necessary for efficient degradation (Kubbutat et al., 1998), although the specific contribution of this region is not known. It seems likely, however, that the activity contributed by the p53 C-terminus is missing in p73, which contains entirely different C-terminal sequences. Other regions of p53 also appear to contribute to the sensitivity to degradation by Mdm2, including sequences in the central DNA binding region encompassed by conserved box II (Kubbutat et al., 1998; Ashcroft et al., 1999). Sequences within this region of p53 have recently been shown to participate in binding to a fragment of the transcriptional co-activator p300/CBP that also binds Mdm2, and in this way p300/CBP may contribute to efficient degradation of p53 (Grossman et al., 1998). There is, however, a second contribution of p300/CBP to regulation of p53. Full length p300/CBP binds to the transactivation domain within the N-terminus of p53 and participates in transcriptional activation by p53, in part by acetylating the C-terminus of p53 to enhance DNA binding (Sakaguchi et al., 1998; Liu et al., 1999). Recently, this interaction of p300/CBP with p53 has been shown to be particularly important for p53 transcriptional activation of Mdm2, and thereby degradation of p53 (Thomas and White, 1998). It would seem that p300/CBP is an important component of the p53 degradation pathway, and p300 (but not CBP) has recently been shown to be required for p53 accumulation in response to DNA damage (Yuan et al., 1999).

Other activities of Mdm2

The participation in the degradation of p53 is an important function of Mdm2, but several lines of evidence suggest that this may not be the only activity of Mdm2 in cells. Of particular interest is the observation that Mdm2 is not completely faithful to p53, and can target the degradation of other proteins that contain Mdm2 binding sites (Haupt et al., 1997). Several important cell cycle regulatory proteins, such as pRB and E2F-1, have been shown in complex with Mdm2, as has the cell fate regulator, Numb (Juven-Gershon et al., 1998). There is evidence that both Numb and E2F1 stability can be negatively regulated by Mdm2 (Juven-Gershon et al., 1998; Blattner et al., 1999), although Mdm2 has also been reported to be associated with enhanced E2F1 activity (Martin et al., 1995; Xiao et al., 1995; Sun et al., 1998). p53 independent activities of Mdm2 both in driving tumor development (Lundgren et al., 1997; Jones et al., 1998) or inhibiting cell growth (Brown et al., 1998) have been described, although whether these relate to an ability of Mdm2 to degrade cellular proteins other than p53 is not yet clear. Other activities of Mdm2 include transcriptional activation functions (Léveillard and Wasylyk, 1997) and the ability to complex ribosomal proteins (Marechal et al., 1994), and potentially reflect an ability to regulate protein expression at the level of translation. Binding to ribosomal proteins may also contribute to the nucleolar localization of Mdm2 seen under some circumstances (see below).

Mdm2 independent degradation of p53

Mdm2 has now been well established as one of the principal regulators of p53 stability, but may not be the only mechanism to target the degradation of p53. Another well established E3 ubiquitin-ligase for p53 contains the cellular E6AP protein in complex with the E6 protein encoded by some genital human papillomaviruses (Scheffner et al., 1993). The E6/E6AP complex targets the degradation of p53 extremely efficiently, both in vivo and in vitro, and cells expressing E6 are severely compromised in their ability to mount a normal p53 response, because the p53 protein cannot be stabilized. Despite the dramatic efficiency with which E6/E6AP degrades p53, the cellular component of this ubiquitin ligase, E6AP, does not appear to play any role in regulating p53 stability in cells that do not express E6 (Beer-Romero et al., 1997; Talis et al., 1998). It would seem that the interaction with E6 changes the substrate specificity of E6AP to allow ubiquitination of p53.

Other cellular proteins also appear to contribute to the degradation of p53 in normal cells, and the interaction of JNK with p53 has been shown to regulate p53 ubiquitination and stability (Fuchs et al., 1998a). JNK-directed degradation is independent of Mdm2 and does not require the kinase activity of JNK. The mechanism by which JNK functions to regulate p53 stability is not yet understood, although it has been suggested that JNK can function as part of a ubiquitin-ligase (Fuchs et al., 1998a), and the relative contribution of JNK to regulation of p53 levels is not clear. JNK1, 2 or 3 deficient mice do not show the early p53 dependent lethality characteristic of Mdm2 deficiency, although this could reflect compensatory activities of the remaining JNK family members.

In addition to degradation through the proteasome, other proteases may also play a role in regulating p53 stability. p53 has been shown to be cleaved by calpain in several systems (Kubbutat and Vousden, 1997; Pariat et al., 1997; Zhang et al., 1997) and the inhibition of calpain in cells results in stabilization of p53. However, the importance of this cleavage in regulating p53 stability in cells has not yet been established.

Stabilization of p53

Rapid degradation of p53 in normal cells is critical to efficiently dampen p53 activity, and the induction of a p53 response is intimately related to the stabilization of the p53 protein. With the understanding that p53 degradation is regulated in large part by Mdm2 came the realization that stabilization of p53 is likely to involve mechanisms to protect p53 from Mdm2. Stabilization of p53 is a common response to many different and diverse forms of stress, including DNA damage, oncogene activation, metabolic changes, hypoxia and changes in pH or temperature (Figure 1). The activation of p53 and inhibition of cell growth in response to these signals is thought to prevent the development and progression of malignant cells, by preventing accumulation of genomic abnormalities and inhibiting the outgrowth of abnormally proliferating cells, or cells growing under abnormal conditions (Levine, 1997). It is becoming clear that each of these stress signals is likely to inhibit Mdm2-mediated degradation of p53, but this is achieved through numerous independent pathways.

Figure 1
figure1

Many stress signals lead to the stabilization of p53, and these signals are likely to lead to inhibition of Mdm2 mediated degradation

Phosphorylation of p53

One of the most obvious ways to protect p53 from Mdm2 is to prevent the interaction between the two proteins, and this could be achieved by modification of either protein in response to an activating signal. Recently, p53 has been shown to be inducibly phosphorylated at a number of sites after various forms of DNA damage (Meek, 1998) and several kinases have been implicated in this process. A plethora of kinases have been shown to phosphorylate residues within the N-terminus of p53 in vitro, including ATM, ATR, DNA-PK, JNK and CKI (Jayaraman and Prives, 1999). Endogenous p53 has been shown to be phosphorylated at several sites following DNA damage, including serine 15, 20, 33 and 37 (Siliciano et al., 1997; Banin et al., 1998; Canman et al., 1998; Shieh et al., 1999), and there is evidence that ATM and ATR can phosphorylate serine 15 in vivo (Khanna et al., 1998; Tibbetts et al., 1999). PKR activity has also been shown to be involved in the phosphorylation of the analogous site in mouse p53 (serine 18) (Cuddihy et al., 1999).

Although p53 is clearly phosphorylated at several sites in response to DNA damage, the exact contribution of each individual modification to stabilization remains unclear. Our understanding of the structural requirements for the p53/Mdm2 interaction (Kussie et al., 1996) indicates that phosphorylation within the N-terminus of p53 could impede binding between the two proteins. Several reports have identified reduced binding between Mdm2 and either phosphorylated p53 proteins or phosphorylated peptides representing the Mdm2 binding region of p53. These studies have suggested a potential role for serine 15 (Shieh et al., 1997), serine 20 (Unger et al., 1999), serine 33 (Fuchs et al., 1998b), or even threonine 18 (Böttger et al., 1999), which remains to be formally identified as a site for phosphorylation in vivo. Phosphorylation at these residues certainly correlates with stabilization of p53 in response to some signals, although the observation that different patterns of phosphorylation occur in response to different stabilizing signals indicates that no individual site is responsible for stabilization in response to all signals. Indeed, studies using p53 proteins in which all the known and potential N-terminal phosphorylation sites have been mutated to non-phosphorylatable residues indicate that phosphorylation is not essential for all forms of DNA damage induced stabilization of p53 (Ashcroft et al., 1999). Nevertheless, ATM activity clearly plays an important role in allowing stabilization of p53 in response to some forms of irradiation or DNA double strand breaks (Kastan et al., 1992; Lu and Lane, 1993; Nakagawa et al., 1999), and loss or inhibition of either ATM or ATR results in a delay in p53 stabilization or inhibition of serine 15 phosphorylation respectively (Siliciano et al., 1997; Khanna et al., 1998; Tibbetts et al., 1999). Taken together, phosphorylation of p53 appears to be indicative of the activation of specific sets of kinases in response to different forms of stress. Each of these kinases could contribute to the stabilization of p53, although p53 itself may not be the only critical target for phosphorylation. Most obviously, Mdm2 has been shown to be phosphorylated (Mayo et al., 1997), possibly leading to an inhibition of Mdm2's ability to bind p53, function as a uniquitin ligase or export p53 from the nucleus. DNA damaging signals that stabilize p53 also lead to the stabilization of E2F1 (Blattner et al., 1999), suggesting that these stress signals lead to the inactivation of Mdm2, and so also inhibit the degradation of other target proteins.

Other mechanisms for the stabilization of p53

Although phosphorylation plays a role in stabilizing p53 in response to some forms of stress, it is now clear that not all p53 activating signals depend on direct phosphorylation (Figure 2). Indeed, insults such as heat shock, oncogene activation or treatment with actinomycin-D, stabilize p53 without significant phosphorylation of serine 15 (de Stanchina et al., 1998; Nakagawa et al., 1999) (Ashcroft and Vousden, unpublished observations). Some activating signals have been shown to specifically inhibit the transcription of Mdm2, thereby reducing Mdm2 protein levels and increasing p53 stability (Arriola et al., 1999) (Blattner et al., 1999) (Ashcroft and Vousden, unpublished observations). The stability of mutant forms of p53 in cancer cells indicates that loss of p53 transcriptional activity results in a reduction of Mdm2 expression and failure to degrade p53 normally. Cytoplasmic sequestration of p53 would result in a similar inability of p53 to activate Mdm2 expression, with consequent stabilization of the p53 protein. In this case, however, the cytoplasmic p53 protein would also fail to activate transcription of other target genes that are necessary to mediate cell cycle arrest and apoptosis, and is therefore likely to be defective in activating the full tumor suppressor response (Moll et al., 1996). Expression of alternatively spliced versions of Mdm2 in tumors have also been correlated with stabilization of p53 (Sigalas et al., 1996; Kraus et al., 1999).

Figure 2
figure2

Inhibition of Mdm2 mediated degradation can occur through several pathways

The best understood of the phosphorylation independent stabilization mechanisms at the moment involves activation of expression of a small tumor suppressor protein called p14ARF in humans, p19ARF in the mouse (Kamijo et al., 1998; Pomerantz et al., 1998; Stott et al., 1998). p14ARF binds directly to Mdm2 in a region distinct from the p53 binding domain, and inhibits the degradation of p53 without preventing the binding. p14ARF functions both by inhibiting the ubiquitin ligase activity of Mdm2 (Honda and Yasuda, 1999) and by sequestering Mdm2 into the nucleolus, thus preventing nuclear export which is necessary for degradation (Weber et al., 1999). As expected from a protein that inhibits Mdm2 activities in this way, expression of p14ARF not only stabilizes p53, but also Mdm2.

The identification of p14ARF leads to the exciting possibility that other Mdm2 interacting proteins may also influence the degradation of p53. Recently, pRB was shown to inhibit the degradation of p53 by direct binding to Mdm2, and in this way pRB could protect p53 apoptotic activity from down regulation by Mdm2 (Hsieh et al., 1999). Interestingly, pRB does not inhibit p53/Mdm2 interaction, and so the p53 stabilized by pRB remains in contact with Mdm2 and fails to regain transcriptional activity. pRB therefore only partially activates p53, allowing apoptosis but not cell cycle arrest. Other proteins that bind p53 may also protect from Mdm2 mediated degradation, and c-Abl has been reported to protect p53 from Mdm2-mediated degradation without inhibiting the p53/Mdm2 interaction (Sionov et al., 1999). There are many other p53 binding proteins (Pietenpol and Vogelstein, 1993), although none has been firmly established yet as a regulator of p53 stability.

Role of p14ARF in stabilization of p53 in response to oncogene activation

Amongst the stress signals that induce p53, abnormal proliferation driven by oncogene activation has recently emerged as one of the most interesting and important. Cell cycle progression depends to a large extent on the activity of the E2F family of transcription factors. Many of the genes necessary for cell growth are regulated by E2F, and activation of E2F occurs at each cell cycle (Dyson, 1998). In normal cells E2F activity is tightly regulated by several mechanisms, and loss of this regulation is a common event in cancer cells (Hall and Peters, 1996). It would appear that abnormal proliferation characteristic of malignant progression is achieved in part by uncontrolled activity of E2F, but in addition to driving proliferation this is also the signal to mechanisms that eliminate cells undergoing such oncogenic changes (Pan et al., 1998; Tsai et al., 1998). One member of the E2F family, E2F1, shows strong apoptotic activities (Nevins, 1998) which are in part reflected by the ability of E2F1 to stabilize p53. This stabilization of p53 is achieved through the direct transcriptional activation of p14ARF, which inhibits Mdm2 as described above (Bates et al., 1998). Other oncogenes, such as Ras, Myc and E1A have also been shown to stabilize p53 through p14ARF (de Stanchina et al., 1998; Palmero et al., 1998; Zindy et al., 1998) and the p14ARF/Mdm2/53 pathway represents an important failsafe mechanism to protect the organism from the outgrowth of abnormally proliferating cells. Interestingly, the observation that E2F1 stability is also regulated by Mdm2 suggests that abnormal E2F1 activity would result in the stabilization of both p53 and E2F1 itself. Studies identifying apoptotic activities of E2F1 that are p53 independent, but sensitize cells to p53 mediated death, suggest that these feedback mechanisms may amplify the apoptotic response to abnormalities in growth.

Conclusion

It is now clear that the regulation of p53 stability is a complex process that is extremely sensitive to many forms of stress. Many pathways can be used to allow stabilization of p53, such as phosphorylation, inhibition of Mdm2 synthesis, cytoplasmic sequestration of p53 or expression of inhibitors of Mdm2 function such as p14ARF (Figure 2). To some extent these mechanisms that stabilize p53 are independent, and loss of p14ARF, for example, does not prevent stabilization of p53 in response to DNA damage (Kamijo et al., 1997). The observation that p14ARF is often lost in tumor cells that retain wild type p53, and the high tumor incidence in mice devoid of p19ARF, indicates strongly that this protein plays an important role in tumor suppression and that activation of p53 in response to proliferative abnormalities is a strong protection from malignant progression (Sherr, 1998).

Many tumors that retain wild type p53 show defects in the pathways to stabilize and activate p53, such as overexpression of Mdm2, expression of the papillomavirus E6 gene or loss of p14ARF. The fact that cells lacking p14ARF retain the ability to activate p53 in response to DNA damage presents some extremely exciting therapeutic possibilities, since these types of tumors might be more sensitive to DNA damage inducing chemotherapeutic drugs than tumors that have lost p53 function directly through mutation. Other therapeutic possibilities include inhibition of the Mdm2/p53 interaction to allow stabilization of p53 and peptides that block binding between the two proteins (Böttger et al., 1997) or antisense inhibition of Mdm2 expression (Chen et al., 1999) have already been shown to lead to the stabilization of p53. Advances such as these are finally allowing us to apply our increasing understanding of the molecular basis of cancer to the rational design of cancer therapy.

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Acknowledgements

We are grateful to members of the Vousden lab for advice and helpful criticisms of this review. This work was sponsored by the National Cancer Institute, DHHS, under contract with ABL.

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Correspondence to Karen H Vousden.

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Ashcroft, M., Vousden, K. Regulation of p53 stability. Oncogene 18, 7637–7643 (1999). https://doi.org/10.1038/sj.onc.1203012

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Keywords

  • p53
  • Mdm2
  • protein stability

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