Oncogene (2007) 26, 2220–2225 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW Are interactions with p63 and p73 involved in mutant p53 gain of oncogenic function?
Y Li and C Prives
Department of Biological Sciences, Columbia University, New York, NY, USA
Although still controversial, the presence of mutant p53 in deletion or frameshift mutations resulting in their lack cancer cells mayresult in more aggressive tumors and of expression, however, many tumor-derived p53 muta- correspondinglyworse outcomes. The means bywhich tions are of the missense variety. These mutations are mutant p53 exerts such pro-oncogenic activityare usually located within the central conserved region of currentlyunder extensive investigation and different p53 that binds to DNA in a sequence-specific manner models have been proposed. We focus here on a proposed and result in either direct loss of DNA contact or gross mechanism bywhich a subset of tumor-derived p53 mut- change of the conformation that no longer permits p53 ants physically interact with p53 family members, p63 and to recognize its wild-type DNA targets (reviewed by p73, and negativelyregulate their proapoptotic function. Vousden and Lu, 2002). Approximately 30% of these Both cell-based assays and knock-in mice expressing tumor-derived p53 mutations affect only six ‘hot-spot’ mutant forms of p53 support this model. As more than half residues (175, 245, 248, 249, 273 and 282). In many cases of human tumors harbor mutant forms of p53 protein, tumor-derived p53 mutants are expressed at far higher approaches aimed at disrupting the pathological interac- levels than wild-type p53 protein due in part to their tions among p53 familymembers might be of clinical failure to be degraded by Mdm2. Related to this, many value. experimental and clinical lines of evidence suggest that Oncogene (2007) 26, 2220–2225. doi:10.1038/sj.onc.1210311 tumor-derived p53 mutants have acquired novel func- tions that promote cancer cell growth. The underlying Keywords: mutant p53; p63; p73; protein–protein inter- mechanisms by which these gain-of-function p53 mu- action tants act, a subject of intense study, can be at multiple levels. For example such mutants might upregulate a specific set of genes promoting cell growth and/or inactivate distinct sets of genes that have tumor suppressor activity. Indeed, according to one model Introduction different p53 mutants might each display unique properties in regulating gene expression (Resnick and The p53 tumor suppressor plays a central role in Inga, 2003). We discuss in this review a hypothesis to regulating cell cycle and apoptosis. Under a variety of explain how mutant p53 promotes pro-oncogenic stress conditions, wild-type p53 protein quickly accu- activities which posits that some mutant p53 proteins mulates in the nucleus and can then transcriptionally can interact with and downregulate the transcriptionally regulate a number of downstream genes that control cell active forms of the p53 homologues, p63 and p73, cycle arrest or apoptosis (reviewed by Vogelstein et al., leading to reduced apoptotic response and radioresis- 2000; Laptenko and Prives, 2006). In addition, wild-type tance in tumor cells. Evidence to support this hypothesis p53 can contribute to apoptosis through transcription- is described and discussed below. independent pathway(s) in the cytosol (reviewed by The p53 gene family consists of three members p53, Chipuk and Green, 2006). Loss of p53 function p63 and p73 that are homologous in three domains: inevitably promotes tumorigenesis and also renders their N-terminal transcriptional activation domain tumor cells resistant to chemo- and radiotherapy. (TAD), central core sequence-specific DNA-binding There are several lines of evidence that p53 functions domain (DBD) and the C-terminally located oligomer- as a canonical tumor suppressor. Notably p53-null mice ization domain (OD). P63 and p73, which generally acquire tumors early with 100% penetrance, highly share more homology with each other than with p53, cancer-prone Li–Fraumeni families carry germline can be expressed as two N-terminal isoforms that either mutant forms of p53, and p53 is among the most contain (TA) or lack (DN) a full TAD through alternate commonly mutated genes in all human cancers. In promoter usage and these two isoforms in turn can each contrast to other tumor suppressors that undergo large have multiple C-termini generated as a result of alternative splicing. In general, the full-length TA Correspondence: Dr C Prives, Department of Biological Science, versions of p63/p73 can exert p53-like activities, whereas Columbia University, New York, NY 10027, USA. the DN versions have the opposite effect (reviewed by E-mail: [email protected] Yang et al., 2002). More recently it was reported that The physical and functional interaction between mutant p53 and p63/p73 Y Li and C Prives 2221 p53 can also be expressed as multiple isoforms differing sufficient to bind p63 or p73 both in vivo and in vitro in N and C-termini (reviewed by Murray-Zmijewski (Strano et al., 2000, 2002; Gaiddon et al., 2001). et al., 2006). The different p53 C-termini, however, are Moreover, either a construct expressing the p73 core quite distinct from those of p63 and p73. DNA binding and OD, or one expressing just the DBD It is still unclear whether and to what extent p63 and of p63, can associate with mutant p53 (Strano et al., p73 play roles in tumor suppression. p63 and p73 2000, 2002). As p63 and p73 are most homologous to knockout mice display defects in development rather each other in their core domains and they were shown to than increased tumorigenesis. Furthermore, p63/p73 bind to the same subset of p53 mutants, it is likely that mutations are not commonly observed in human their core domains are the critical if not sole binding tumors. Nevertheless, several lines of evidence suggest surface for mutant p53. that p63 and p73 can also mediate cellular responses to How might such interactions occur? A number of DNA damage agents and have potential tumor suppres- results collectively suggest that conformational changes sion activity in vivo. First, when overexpressed, TAp63/ in the p53 core domain are responsible for its interaction p73 can activate a number of common p53 responsive with p63/p73. First, most p53 hot-spot mutants undergo genes involved in cell cycle arrest and apoptosis structural changes in the DBD as determined by nuclear (Kaghad et al., 1997; Osada et al., 1998; Yang et al., magnetic resonance spectroscopy (Wong et al., 1999). 1998; Wu et al., 2003; Lokshin et al., 2005). Second, There is also a strong correlation between the ability of endogenous TAp73 can be stabilized by DNA-damaging mutant p53 to interact with p63/p73 and their reactivity agents and its ablation can result in chemoresistance to the conformation sensitive monoclonal antibody (Bergamaschi et al., 2003; Irwin et al., 2003; Urist et al., PAb240 (Gaiddon et al., 2001). This antibody recog- 2004). Although less explored, endogenous TAp63 can nizes a cryptic epitope within the core domain when p53 also determine chemotherapeutic efficiency (Gressner is unfolded and therefore reflects an altered conforma- et al., 2005). Third, Flores et al. (2002) showed that p63 tion of the protein (discussed by Cho et al., 1994). and p73 are required by p53 to activate a few Moreover, wild-type Xenopus laevis p53 protein that was proapoptotic genes in mouse embryo fibroblasts (MEFs) shown to be intrinsically temperature sensitive at 371C, expressing adenoviral E1A. Finally, in one genetic binds to both human p73 and the heat-shock protein background mice heterozygous for p63 and p73 can hsp70 in a temperature-dependent manner (Bensaad developtumors (Flores et al., 2005). Nevertheless, in et al., 2003). In fact, some p53 mutants with conforma- contrast to p63 or p73, the central role of wild-type p53 tional distortion can associate with hsp70 protein in protection from cancer is unequivocal. (Gannon et al., 1990) and some of these can also interact with p73 (Gaiddon et al., 2001). Furthermore, immunopurified wild-type p53 protein contains a frac- tion that is conformationally changed during the A subset of p53 mutants can interact with p63 and p73 procedure and is both recognized by PAb 240 and can interact with p73 (Gaiddon et al., 2001). In addition, Biochemical studies have revealed that the tetrameriza- wild-type p53 prepared under harsh conditions or upon tion domains of p63 and p73 can hetero-oligomerize repeated freeze and thaw cycles that partially denature with each other but neither can form heterotetramers proteins can associate with p73 (Bensaad et al., 2003). with p53 (Davison et al., 1999). Despite this it has been Despite indications that the main determinant for shown that a number of p53 mutants can associate with interaction with p63 and p73 is an unfolded p53 core either p73 or p63 as evidenced by co-immunoprecipita- domain there are many observations suggesting that this tion assays when they are either ectopically or endogen- conclusion may be an oversimplification. For example, ously expressed (Di Como et al., 1999; Marin et al., unlike full-length p53, several versions of truncated 2000; Strano et al., 2000, 2002; Gaiddon et al., 2001; wild-type p53 can interact with p73 when they are Bergamaschi et al., 2003; Irwin et al., 2003). Both coexpressed in insect cells (Gaiddon et al., 2001). These ‘conformation’ mutants (e.g. R175 and G245) and include p53 variants with a wild-type core domain but ‘contact’ tumor derived p53 mutants (e.g. R248, R273, lacking either the OD, the N-terminal 96 amino acids or R283) have been reported to associate with p63/p73. the C-terminal 30 amino acids, suggesting that such Furthermore, purified mutant p53 and p63/p73 can bind deletions could impose long range influence on the to each other in vitro, strongly indicating that such conformation of the core domain. Even though it is interaction is direct (Gaiddon et al., 2001; Strano et al., assumed that p53 contact mutants disrupt protein– 2002). Although only a subset of p53 mutations have DNA interactions without gross conformational been tested so far, the fact that some hot-spot mutants changes, some of the contact mutants are capable of are capable of interacting with and inactivating p63/p73 interacting with p63/p73 (e.g. R248, R273, R283). They suggest that a significant portion of mutant p53 proteins too may exhibit subtle structural distortion to expose a in tumors could participate in complexes with the p53 binding site for p63/p73. Indeed the R248 mutation has family members. been found to alter the structure of the DBD (Wong Interestingly the interaction between mutant p53 and et al., 1999). Most intriguingly two groups have reported p63/p73 is very likely to be through their respective that the binding affinity of mutant p53 for p73 (as well central conserved core domains. Deletion analyses have as p63) is affected by a common p53 polymorphism at shown that the core domain of mutant p53 alone is codon 72 (R72 or P72; Marin et al., 2000; Bergamaschi
Oncogene The physical and functional interaction between mutant p53 and p63/p73 Y Li and C Prives 2222 et al., 2003). These studies indicate that p53 mutants enhances the cellular response to drug-induced cell with R72 can associate with p73 more efficiently than death. Although future studies are required to find out the same mutants harboring P72. Further studies are the extent of the contribution of p63 and p73 to this needed to investigate whether the codon 72 polymorph- increased chemosensitivity, these reports have provided ism has a direct impact on the core domain conforma- a plausible link between mutant p53 binding to p73 and tion, makes an additional contact with p73, or requires a decreased chemosensitivity of cells. Taking this other proteins in the cell to mediate the effect. It will be further, a clinical study showed a correlation between crucial to determine whether purified mutant p53 the codon 72 polymorphism in p53 mutants and the proteins with either codon 72 polymorphism can interact therapeutic response of a subset of head and neck differently with purified p63/p73 proteins in vitro. cancers (Bergamaschi et al., 2003). Tumors in those As others have not observed a similar correlation, it is patients who responded worse to chemoradiotherapy possible that multiple determinants such as cell type generally retain the R72 version of mutant p53 that might modulate the influence of this polymorphism binds better to p73. It is acknowledged that the clinical (Gaiddon et al., 2001; Willis et al., 2003). data implicating the R72 variant as being more What remains to be determined is the nature of the deleterious could result from other properties that this surfaces on the unfolded mutant p53 core domain that change confers upon mutant p53, just as it has with make contact with p63 and p73 and whether the regions wild-type p53. of the wild-type p63 and p73 cores that interact with Two studies using mouse models have also provided mutant p53 are distinct from that of wild-type p53. It important corroborating evidence in vivo showing that may be relevant that the core domains of wild-type p53 mutant p53 promotes tumorigenesis and that it may do and p73 display significant differences in the exposures so through downregulating its p53 family members of their cysteine residues and their ability to bind zinc (Lang et al., 2004; Olive et al., 2004). These groups (Lokshin et al., 2007). generated p53 mutant mice with mutation at codon 170 (Lang et al., 2004; Olive et al., 2004) as well as codon 270 (Olive et al., 2004). These are the murine equivalents of human p53 R175H and R273H hot-spot mutants, Mutant p53 interactions with p63 and p73 have functional respectively. Importantly, mutant p53 knock-in mice outcomes have different phenotypes from the p53 knockout mice in terms of tumor spectrum and increased metastasis. Whatever the structural basis for the association of Some of their new phenotypes are reminiscent of those mutant p53 with its homologues, several studies have doc- seen in mice losing one copy of both p53 and p63/p73, umented decreased transcriptional activities of p63/p73 and therefore could be in part owing to the inactivation and their ability to induce growth suppression and of p63/p73 pathway by mutant p53 in vivo (Flores et al., apoptosis when in the presence of mutant p53 (Di Como 2005). This hypothesis is supported by the following et al., 1999; Marin et al., 2000; Strano et al., 2000, 2002; experiments. First, mutant p53 proteins were found to Gaiddon et al., 2001; Bergamaschi et al., 2003). be associated with endogenous p63 and p73 in tumor Importantly, these studies have indicated a good cells from these mutant p53 mice (Lang et al., 2004; correlation between the efficiency of binding to and Olive et al., 2004). Second, silencing of mutant p53 inactivation of p63/p73 by mutant p53. As mutant p53 expression in these tumor cells stimulated the expression interacts with the core DBD of p63/p73, it is conceivable of p53 family target genes, most likely reflecting an that p63 and p73, when bound to mutant p53, might be enhanced activity of endogenous p63/p73 in the absence inefficient at recognizing their own DNA targets, as was of mutant p53 (Lang et al., 2004). Third, downregula- previously reported using a DNA-binding electrophore- tion of p63/p73 in p53-null MEFs stimulated DNA tic mobility shift assay (Marin et al., 2000; Strano et al., synthesis and transformation potential to levels similar 2000). Moreover, using a chromatin immunoprecipita- to those in mutant p53 MEFs (Lang et al., 2004). It is tion assay, it was demonstrated that the recruitment of relevant that loss of p63 has been recently shown to endogenous p63 to its target genes such as p21, 14-3-3s upregulate genes involved in invasion and metastasis and bax is impaired in cells expressing either endogen- (Barbieri et al., 2006). This could in part explain the ous or ectopic mutant p53 (Strano et al., 2002). reasons for the increased metastasis observed in mice Taking these findings into a more physiological expressing mutant p53. context, results from two groups support the possibility that mutant p53 can hamper the cellular chemoresponse through inhibiting endogenous p63 or p73 (Bergamaschi et al., 2003; Irwin et al., 2003). Specifically, a number of Mutant p53 and p63/p73: what lies ahead? human tumor cell lines are more resistant to chemother- apeutic drugs when they express ectopic or endogenous As described above a significant body of work suggests mutant p53 capable of binding to p73. Importantly, cells that some of the common forms of mutant p53 might exert with those p53 mutants that can bind better to p73 their pro-oncogenic activity in part through their interac- usually have a higher resistance to chemotherapeutic tions with p63 and p73. To further understand the drugs. Reciprocally, downregulating the expression of relationship between mutant p53 and p63/p73 the follow- mutant p53 using small-interfering RNA (siRNA) ing questions might be worthy of future investigation.
Oncogene The physical and functional interaction between mutant p53 and p63/p73 Y Li and C Prives 2223 How many molecules ofmutant p53 are required to (Gaiddon et al., 2001). If this is a general phenomenon, it inactivate p63/p73? implies that there may be sequences outside of the core Although the answer to this is as yet unclear, as noted domain that are unique to the TA isoforms of p63 and above, mutant forms of p53 often accumulate to high p73 that facilitate their interaction with mutant p53 or levels in tumor cells. It is conceivable that a high ratio of alternately that the short sequence unique to the DN mutant p53 to p63/p73 is required for the inhibitory role isoform weakens its interactions with mutant p53. It also of mutant p53. It is therefore important to assess how suggests the possibility of unifying the current possible much p63 or p73 protein is normally present in tumor modes by which mutant p53 proteins can act. They can cells. In fact, in HCT116 cells, where this was carefully directly promote pro-proliferative gene expression assessed, endogenous wild-type p53 is present at about a through their interactions with NF-Y proteins and inhibit 20- to 30-fold molar excess over wild-type p73 even after the anti-proliferative properties of the TA p63/p73 treatment of cells with DNA-damaging agents that lead without hampering the opposing activity of their DN to increased levels of both proteins (Lokshin et al., 2005). counterparts. There are clearly some important experi- Additionally, we have found that in human immortalized ments that need to be performed to further elucidate the keratinocytes (HaCat) mutant p53 is present at greater relationshipbetween mutant p53 and the different than a 20-fold excess over p63 (Li, Neusch and Prives, isoforms of p63 and p73. unpublished data). In support of this, at least half of the endogenous p73 in HaCat cells was found to bind to Do mutant p53 proteins affect the ability of p63/p73 to mutant p53, whereas only a small portion of the mutant interact with other proteins that regulate their activities? p53 associates with p73, suggesting that mutant p53 is A plethora of binding partners have been identified that more abundant than p73 in the cell (Marin et al., 2000). interact with p53 and a growing number of proteins It is therefore likely that a considerable surfeit of mutant have also been found to bind to p63 and/or p73. p53 is needed for it to sequester the majority of p63 or Particularly relevant are the apoptosis stimulating p73. This may account for the observations of Willis protein of p53 (ASPP) family proteins, ASPP1 and et al. (2003) who, using an elegant dual inducible ASPP2, that have been shown to bind to and stimulate promoter system to express both wild-type p73 and the apoptotic function of p63 and p73 (Bergamaschi mutant p53 (R175H), failed to see an inhibitory effect of et al., 2004) as had been previously shown for p53 mutant p53 on p73b over a range of mutant p53/p73 (Samuels-Lev et al., 2001). As the ASPP2 protein binds ratios. Possibly they did not reach the same ratio of to the core-DBD of p53, it is quite likely that the central mutant p53 to p73 experimentally as found in some regions of p63 and p73 are also where ASPP proteins tumor cells. Further, the cells they used (H1299 cells) interact (Gorina and Pavletich, 1996). It would therefore may be unique in requiring massively higher amounts of be interesting to determine whether the stimulation of mutant p53 obtainable only by transient transfection. p63/p73 by ASPP proteins can also be negatively affected by mutant p53. If so, mutant p53 may have a dual impact on p63/p73 by both blocking their Can the DN p63/p73 isoforms be regulated by mutant p53? interaction with DNA and some regulatory proteins The assumption that mutant forms of p53 bind to the such as the ASPPs. Other proteins have also been shown core domains of p63 and p73 leads to a potentially to interact with p63 and p73 including YAP and SSRP1 complicated scenario. The above-mentioned inhibitory although they do not apparently interact with their core effects of mutant p53 were shown to act upon the TA domains (Strano et al., 2001; Zeng et al., 2002). It isoforms of p63 and p73 that are proapoptotic. It remains cannot be excluded that mutant p53 may counteract to be addressed whether mutant p53 can also inhibit the these interactors or, reciprocally, they may modulate the function of DN p63/p73 proteins. If this were the case ability of mutant p53 to downregulate p63 and p73. then one would have to take into account the fact that Thus, further studies may reveal a second level of DN p63/p73 proteins can have pro-proliferative and regulation of p63 and p73 by mutant p53 by affecting possibly oncogenic activity. In fact, DNp63, like some their interactions with other proteins. p53 mutants, promotes the survival of squamous cell carcinoma (SCC) by blocking the TAp73 pathway (Rocco et al., 2006). In addition, many SCC cells express Do mutations within the central domains ofp63 and p73 both mutant p53 and DNp63 (Hibi et al., 2000). affect the activity of wild-type p53? Moreover, one recent study revealed that the hot-spot Although mutations in p63/p73 genes are not readily R175H mutant p53 can induce the expression of DNp63 found in cancer, p63 gene mutations are associated with after a subset of DNA damage treatment including at least five inherited human developmental diseases that doxorubicin (Lanza et al., 2006). This phenomenon seems display phenotypes such as limb malformation, facial to be mediated by CCAAT box and NF-Y protein, and is cleft and ectodermal dysplasia (reviewed by Brunner consistent with another study showing that mutant p53 et al., 2002). Of note, germline mutations found in one of can interact with NF-Y transcription factors to stimulate these syndromes, the ectrodactyly-ectodermal dysplasia the expression of proliferative cell cycle genes after DNA clefting, are clustered in the DBD of p63. More strikingly, damage (Di Agostino et al., 2006). Regardless, in one many of these mutations correspond exactly to the hot- experimental setting overexpressed DNp63 had much spot mutants in p53 gene: p63 R204, R279, R280 and lower binding affinity than TA p63 to mutant p53 R304 mutants are analogous to p53 R175, R248, R249
Oncogene The physical and functional interaction between mutant p53 and p63/p73 Y Li and C Prives 2224
Mutant p53
p63/p73 Downregulating mutant p53
Mutant p63/p73 p53 Mutant p63/p73 p53 p63/p73 x Overexpressing p63/p73
Binding site
target genes: p21, Bax, Puma, Noxa, etc. Mutant p53 p63/p73 Blocking mutant p53 interaction with p63/p73 using peptidomimetics or small molecules Figure 1 Strategies to overcome mutant p53 interaction with p63/p73. Multiple approaches can be exploited to enhance the activity of p63/p73, including ablating the expression of mutant p53 proteins, overexpressing p63/p73 proteins, or disrupting the physical interaction between p53 and p63/p73 with peptidometics or small molecules.
and R273, respectively. As with p53, such mutants overexpressing the proapoptotic p63/p73 proteins or abolish the ability of p63 to interact with DNA (reviewed disrupting the direct protein–protein interaction be- by van Bokhoven and Brunner, 2002). As p63 and p73 tween mutant p53 and p63/p73 using peptidomimetics can bind each other through their OD, it is possible that or small molecules (Figure 1). Of note, those small these p63 mutants may serve as dominant-negative molecular compounds that can reactivate mutant p53 by regulators of p73 as well as p63 (Davison et al., 1999). restoring it to wild-type conformation can also poten- In addition, it will also be of interest to test whether these tially release p63/p73 (reviewed by Wiman, 2006). Such p63 mutants can reciprocally bind to and regulate p53. compounds are potentially exciting as they may achieve the dual purpose of bringing back the activity of both p53 and its family members. Clinical implications In summary, results obtained from cell culture, mouse models and clinical correlation have implied that some As p73 and p63 are involved in both DNA damage mutant p53 proteins have gained a novel function by induced apoptosis and may be implicated in tumor inactivating p63/p73. These studies have pointed the suppression, efforts aimed at liberating p63/p73 from way towards future basic and translational research blockade by mutant p53 might have therapeutic values directions. It is hoped that upcoming studies will shed in cancer treatment. Such approaches can include new light on the meaning of mutant p53 regulation of its downregulating mutant p53 via siRNA technology, siblings p63 and p73.
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