(2007) 26, 2212–2219 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW Mutant p53: an oncogenic

S Strano1, S Dell’Orso1, S Di Agostino1, G Fontemaggi1,2, A Sacchi1 and G Blandino1,2

1Department of Experimental Oncology, Regina Elena Institute, Via delle Messi d’oro, Rome, Italy and 2Rome Oncogenomic Center, Regina Elena Cancer Institute, Via delle Messi d’oro, Rome, Italy

Inactivation of tumor-suppressor is one of the key phorylation, , prolyl-isomerization and su- hallmarks of a tumor. Unlike other tumor-suppressor moylation are the most characterized post-translation genes,p53 is inactivated by missense in half of modifications of p53 family members that impact on all human . It has become increasingly clear that the their transcriptional activity either by potentiating or resulting mutant p53 do not represent only the dictating the selectivity in the activation of the proper mere loss of wild-type p53 tumor suppressor activity,but target (Jayaraman and Prives, 1999; Costanzo gain new oncogenic properties favoring the insurgence,the et al., 2002; Brooks and Gu, 2003; Xu, 2003; Bode and maintenance,the spreading and the chemoresistance of Dong, 2004; Strano et al., 2005). The net result of this malignant tumors. The actual challenge is the fine deci- selective transcriptional activation is the maximization phering of the molecular mechanisms underlying the gain of of the efficacy of the anti-tumoral effects.To date, the function of mutant p53 proteins. In this review,we will set of p53 transcriptional target genes is also shared by focus mainly on the transcriptional activity of mutant p53 and p63. proteins as one of the potential molecular mechanisms. To As shown recently, it is conceivable that p73 and p63 date,the related knowledge is still quite scarce and many of can transcriptionally activate specific genes that are not the raised questions of this review are yet unanswered. target of wild-type (wt) p53 (Fontemaggi et al., 2002; Oncogene (2007) 26, 2212–2219. doi:10.1038/sj.onc.1210296 Blint et al., 2002; Kartasheva et al., 2003; Stiewe et al., 2003; Lapi et al., 2006). This could represent, at least Keywords: mutant p53; transcription; interaction; sig- partially, the molecular basis of the different phenotypes nature; chip of the respective p53 family members deficient mice. p53-deficient mice develop normally, but develop spontaneous tumors, mainly sarcomas and lymphomas (Jaks et al., 1994; Purdie et al., 1994; Donehower, 1996). Conversely, p73 and p63 knockout mice exhibit severe Introduction developmental defects and do not spontaneously devel- op tumors (Mills et al., 1999; Yang et al., 1999, 2000). Many proteins elicit their anti-cancer effects through the Whereas p53 is mutated in almost half of all human transcriptional activation of target genes, whose reg- cancers (http://.iarc.fr/p53), p73 and p63, despite ulatory regions contain specific binding sites.Among extensive effort, have been found mutated very rarely them, a pivotal role in tumor suppression is played by in human tumors (Sunahara et al., 1998; Takahashi the recently established p53 family.It consists of a group et al., 1998; Kaelin, 1999; Levrero et al., 2000; Yang and of proteins, whose oldest and the most studied member, McKeon, 2000; Olivier et al., 2002). Altogether, these p53, was identified more than 20 years ago (Lane and findings indicate that among the p53 family members, Crawford, 1979; Linzer and Levine, 1979; Oren and p53 has been selected as a canonical tumor-suppressor Levine, 1983; Beinz et al., 1984), whereas its homologs gene whose inactivation certainly gives an advantage to p73 and p63 and their related and truncated spliced the development and the maintenance of a cancer (Lowe forms have been characterized in the last few years et al., 2004). Unlike other tumor-suppressor genes, (Kaghad et al., 1997; Schmale, 1997; Osada et al., 1998; whose inactivation results in the absence or in the Senoo et al., 1998; Augustin et al., 1998; Trink et al., presence of truncated proteins, p53 generates abundant 1998; Yang et al., 1999). The basic modular structure of full-length mutant proteins.This review aims to discuss p53 family members comprises a N-terminal transcrip- some of the open questions regarding the origin and the tional activation domain, a central DNA-binding function of mutant p53 proteins with a special focus on domain and a C terminus with oligomeric and regula- the transcriptional activity of human tumor-derived p53 tory activities (McKinney and Prives, 2005).The gain of function mutants. transcriptional activity of p53 family members is mainly regulated at the posttranslational level.Indeed, phos- Mutant p53 proteins: who are they?

Correspondence: Dr G Blandino, Department of Experimental Oncology, Rome Oncogenomic Center, Regina Elena Cancer Institute, The vast majority of p53 mutant proteins derive from Via delle Messi d’oro, 156, 00158 Rome, Italy. missense mutations occurring mostly within the DNA- E-mail:[email protected] binding domain of p53 (Hollestein et al., 1991; Hussain Mutant p53: an oncogenic transcription factor S Strano et al 2213 and Harris, 1998; Prives and Hall, 1999).Mutant p53 extensive nuclear localization of mutant p53 proteins proteins are abundantly present in cancer cells of (Soussi, 2005).As a consequence, the mechanisms various histotypes ranging from lung, colon, breast to regulating the nuclear/cytoplasmic shuttling of wt-p53, some heamopoietic malignancies (Nigro et al., 1989; whose fine-tuning plays an important role on its stability, Soussi, 2000).They are peculiarly characterized by a might be altered in cells bearing mutant p53 proteins prolonged half-life compared with that of the wt-p53 (Moll et al., 1992; Moll and Petrenko, 2003). Structural and by the inability to recognize wt-p53 DNA- studies have allowed to classify p53 mutant proteins in binding sites (Figure 1) (Sigal and Rotter, 2000; Cadwell two large categories (Cho et al., 1994; Bullock and and Zambetti, 2001).The extent the half-life of mutant Fersht, 2001; Joerger et al., 2005): (a) DNA contact- p53 varies among the diverse human tumor-derived p53 defective mutants (His273, Trp248), which include those mutants.There is yet scarce evidence to allow a mutants whose impacts on the residues classification of mutant p53 proteins according to their composing the DNA/protein interaction surface and (b) specific half-life.The molecular basis of the prolonged structure-defective mutants (His175, His179), whose half-life of mutant p53 proteins needs to be still point mutation determines an important conformational understood.It might partially depend on the inefficient alteration.The attempt to verify whether the structural degradation exerted by the E3 ligase , classification of p53 mutants reveals similar differences whose gene is a direct transcriptional target of wt-p53. in terms of biological activities has been quite difficult Consequently, its activation is impaired in cells carrying to tackle. In vitro studies have shown that the over- mutant p53 proteins (Haupt et al., 1997; Kubbutat et al., expression of conformational p53 mutants renders cell 1997; Midgley and Lane, 1997; Bushmann et al., 2000; cultures more resistant to etoposide, whereas DNA Strano and Blandino, 2003; Lain and Lane, 2005). defective mutants increases the resistance to cisplatin Recent evidence derived from p53 knock-in mice have (Gualberto et al., 1998; Li et al., 1998; Blandino et al., shown that mutant p53 proteins are unstable in normal 1999; Sigal and Rotter, 2000).The presence of conforma- tissues (Lang et al., 2004; Olive et al., 2004). This tional mutants has been associated with strongly favors the hypothesis that the tumor cell patients, whose relapse after conventional chemo- context contains additional physical or chemical factors therapy occurred more frequently when compared with contributing to the increased half-life of mutant p53 patients carrying DNA contact defective p53 mutants proteins.The latter might be gathered in large and yet (Aas et al.,1996;Bernset al., 2000; Geisler et al.,2003). unknown protein complexes that make mutant p53 Altogether, these findings strongly indicate that mutant inaccessible to the protein degradation machinery.A p53 proteins do not represent the mere loss of wt-p53 certain contribution to the stability of mutant p53 could activities, but gain new additional oncogenic functions be also ascribed to its peculiar nuclear localization. which contribute to the development, maintenance, Indeed, immunohistochemical analysis of tumor samples spreading and resistance to anti-cancer treatment of a accompanied by gene sequence analysis have revealed tumor.

a WTp53 Mutant p53

mp53 p53 p53 p53 p53 p53 p53 p53 p53 p53 p53 p53 Half life: 1-24 h Half life: 6-20 minutes

b mp53 p53

p53 consensus p53 consensus

DNA binding and No DNA binding on transcriptional activity p53 consensus

DNA damage DNA p53 damage mp53 Growht arrest Apoptosis Senescence Growht arrest Senescence Chemoresistence Figure 1 wt-p53 versus mutant p53: two sides of the same coin.The half-life and the ability to bind specifically to DNA are hallmarks which distinct wild-type from mutant p53 proteins.

Oncogene Mutant p53: an oncogenic transcription factor S Strano et al 2214 Mutant p53 proteins: how do they function? gain-of-function activity, and might disclose new ther- apeutic targets for innovative anti-cancer treatments; Given that some mutant p53 proteins exert a gain of (b) Levine’s group originally reported that p53 mutant, function, the focus of intense research in the p53 field is whose two critical residues at the N terminus were the elucidation of the molecular mechanisms underlying mutated, loses its gain-of-function activity (Lin et al., this activity (Haley et al., 1990; Dittmer et al., 1993; Lin 1995).-wide approaches have shown that et al., 1995; Vousden and Lu, 2002; Monti et al., 2005). mutant p53 is capable of modulating the expression of To date, mutant p53 proteins might work through the large patterns of transcripts (Figure 2).These findings following molecular scenarios: (a) mutant p53 interacts, indicate that mutant p53 might function as a transcrip- sequesters and inactivates proteins whose activities are tion factor capable to turn on and off specific set of closely connected to anti-tumoral effects ranging from genes in response to different stimuli (Margulies and growth arrest to apoptosis induced by anti-cancer Sehgal, 1993; Subler et al., 1994; Tsutsumi-Ishii et al., treatments.p73 and p63 have turned out to be protein 1995; Ludes-Meyers et al., 1996; Deb et al., 1998; targets of p53 gain-of-function mutants (Di Como et al., Frazier et al., 1998; Lee et al., 2000; Iwanaga and Jeang, 1999; Marin et al., 2000). Indeed, the binding to mutant 2002; Scian et al., 2004, 2005; Mizuaray et al., 2006). p53 strongly defeats p73- and p63-mediated transcrip- Consequently, mutant p53 might trigger different path- tion and apoptosis (Strano et al., 2000; Irwin et al., ways that represent the molecular basis of the large 2003).The in vivo recruitment of both p73 and p63 to spectrum of gain-of-function activities, which ranges the regulatory regions of their target genes is severely from the resistance to anticancer treatments to genomic impaired in mutant p53-expressing cells.Of note, the instability and increased metastasis.Despite rapidly core domain of mutant p53, that has been regarded as accumulating evidence, the knowledge of the molecular ‘functional dead’ due to its inability to recognize the wt- details of the transcriptional activity of mutant p53 is p53-binding site, is sufficient for the binding to p73 and still very scarce; (c) recent work by Di Agostino et al. p63 (Gaiddon et al., 2001; Strano et al., 2002; Strano (2006) has shown that the integration of the previously and Blandino, 2003).Thus, it might serve as a protein– described molecular scenarios might play a role in the protein interaction module, whose activity contributes gain of function of mutant p53.The latter physically to the gain of function.It is conceivable to believe that interacts with the transcription factor NF-Y, whose the identification of novel mutant p53-interacting DNA-binding consensus sequences are present in the proteins might allow, at least partially, the comprehen- regulatory regions of many key genes involved in the sion of the molecular mechanism underlying mutant p53 regulation of the (Figure 3).Furthermore,

Mutant p53 trascriptional activity

Array analysis a mp53

Transcription by

for mutant p53

Mutant p53 Modulated genes b MAD1 LAMP7-E1 mp53 TF MDR-1 Fibronectin EGF-R Calretinin TF CD97Fas D3 EGR1 Nars TF Consensus GEF-H1 c- DSCR-1 IGFBP6 MIPDH2 Complex with Transcription Factor for binding to DNA …… and others

Figure 2 Models for mutant p53 transcriptional activity.( a) Mutant p53 binds the regulatory regions of its target genes through a specific and yet unknown DNA-binding consensus sequence; (b) mutant p53 interacts with a specific transcription factor that drives its gene target specificity.

Oncogene Mutant p53: an oncogenic transcription factor S Strano et al 2215 HDAC1 p300 DNA damage

HDAC1 mp53 YA mp53 YA YB YC YB YC

p300

mp53 YA YB YC

p300 mp53 YA YA Cdk1 YB YC cdc25c CCAAT

Figure 3 The mutant p53/NF-Y connection.In response to DNA damage, the protein complex mutant p53-NFY recruits p300 and assembles on the promoters of NF-Y target genes. mutant p53 is recruited in vivo to such regulatory regions many issues as discussed in this paragraph.Being through the physical interaction with the transcription accepted that wt-p53 is a well-known bona-fide tran- factor NF-Y (Figure 3).Altogether, these results show scription factor, whose specific DNA-binding consensus that the repertoire of the genes regulated by p53 gain-of- sequence, target genes and transcriptional signature function mutants can be dictated by the specific have been identified, the reciprocal characterization for interaction partner; (d) original work from Deppert’s mutant p53 is still scarce. lab has shown that mutant p53 tightly associates with the nuclear matrix in vivo, and with high affinity with nuclear matrix attachment region DNA in vitro (Will DNA-binding consensus sequence et al., 1998; Koga and Deppert, 2000; Gohler et al., Chromatin immunoprecipitation (ChIP) experiments 2005; Kim and Deppert, 2006).These findings suggest have recently and clearly shown that mutant p53 can that mutant p53 interacting with key structural compo- be recruited in vivo onto regulatory regions of diverse nents of the nucleus exerts its gain-of-function activity genes (Weisz et al., 2004; Di Agostino et al., 2006; through the perturbation of the nuclear structure and Zalcenstein et al., 2006). Despite this, the question function. whether these genes are canonical transcriptional targets The molecular scenarios (c) and (d) suggest that the of p53 gain-of-function mutants is still unanswered.To number of the potential transcriptional targets of date, the experimental efforts to identify a specific mutant p53 could be quite large, and consequently the DNA-binding consensus sequence for mutant p53, if complexity of the triggered biochemical pathways any exists, have failed.If mutant p53 is unable to bind considerably high. directly to DNA, its presence onto promoter regions might occur as a member of large transcriptional competent protein complexes.Recent evidence indicates that mutant p53 is present onto promoter regions Is mutant p53 a bona-fide transcription factor? together with DNA-binding proteins, acetylases and/ or deacetylases (Di Agostino et al., 2006). The selective There is no exhaustive answer to this question.It recruitment of acetylates or deacetylates in response represents the focus of intense research which to date to DNA damage dictates transcriptional activation has only produced some information and has left open or repression of target genes (Figure 3).Further

Oncogene Mutant p53: an oncogenic transcription factor S Strano et al 2216 experimental work through sequential re-ChIP will evaluation of in vivo promoter occupancy by a certain eventually confirm the existence of mutant p53 contain- transcription factor (Wu et al., 2006). The application of ing transcriptional competent complexes onto regula- this technique could be extremely useful for a further tory regions of target genes.The type of mutant p53 establishment of the transcriptional activity of p53 gain- functional contribution to the activity of the transcrip- of-function mutants.Indeed, mutant p53-immunopreci- tional competent complex is under intense investigation. pitated chromatin derived from diverse cancer cell lines Mutant p53 could take part into the transcriptional core might be used to probe genome-wide promoter chips as of the complex through its intact N terminus, or well as low density and promoters-oriented chips (Buck alternatively by favoring the recruitment of other and Lieb, 2004).The analysis of genome-wide promoter members required for the transcriptional activity of chips will allow the identification of novel transcrip- the protein complex.Recent evidence shows that mutant tional target genes whose regulatory regions are bound p53 is necessary for the recruitment of p300 to the in vivo by mutant p53.The results raised through the transcriptional competent complex (Di Agostino et al., analysis of low-density promoter-oriented chips might 2006).Although many evidences have clearly shown allow the validation of a mutant p53 transcriptional that post-translational modifications such as serine/ signature to be tested in different cancer cell contexts threonine phosphorylation, acetylation, prolylisomeri- carrying diverse human tumor-derived p53 mutants and zation and sumoylation increase the DNA-binding and upon different types of stimuli. the transcriptional activity of wt-p53 (Bode and Dong, 2004), the impact of these events on mutant p53 transcriptional activity has been evaluated poorly. Perspectives Pattern of target genes There is sufficient evidence in vitro and in vivo to Microarray analyses have shown that the overexpres- establish an oncogenic role for some human tumor- sion of mutant p53 in different cell lines is capable to derived p53 mutants (Lang et al., 2004; Olive et al., modulate the expression of many transcripts (Hoh et al., 2004; Di Agostino et al., 2006). As p53 mutants are 2002; O’Farrel et al., 2004; Scian et al., 2004; Weisz present in almost half of human cancers, the possibility et al., 2004; Tepper et al., 2005; Zalcenstein et al., 2006). to tackle and abolish their oncogenic effects is un- Although a growing pattern of target genes has been doubtedly important for a successful treatment of established for wt-p53 and other transcription factors human tumors.To fulfil such objective, a detail knowl- closely linked to cancer, the definition of a group of edge of the molecular mechanisms underlying gain of potential mutant p53 target genes needs to be solved yet. function of mutant p53 is a necessary step.Among The issue is very difficult to tackle due to the them, the comprehension of the transcriptional activity heterogeneity of p53 mutants, each one of which of mutant p53 will contribute to unveil biochemical potentially could represent a specific transcription factor pathways whose selective targeting might turn out very activating a peculiar pattern of genes only partially useful for the treatment of mutant p53 human cancers. overlapping with that of other gain of function p53 mutants.A comparative bioinformatical analysis of the existing microarray data for mutant p53 might be very Acknowledgements helpful to identify a restricted pattern of genes whose modulation could be further investigated in diverse cell This work was supported by the Italian Association for Cancer contexts carrying mutant p53. Research (AIRC), Ministero della Sanita` , MIUR-FIRB Italy, Italy-USA and the European Community (EC) ‘Active p53 and Mutant p53’ consortia.This publication reflects the Transcriptional signature authors’ views and not necessarily those of the EC.The EC There is growing evidence that ChIP on chip is a is not liable for any use that may be made of the information very powerful technology that allows genome-wide contained herein.

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