Mutant P53: from Guardian to Fallen Angel?

W Deppert

Heinrich-Pette-Institut fu¨r Experimentelle Virologie und Immunologie, Tumor Virology, Hamburg, Germany

Oncogene (2007) 26, 2142–2144. doi:10.1038/sj.onc.1210276 gained further acceptance after the publication of a Nature Genetics paper in 1993 by Dittmer et al. (1993), where the term ‘gain of function’ appeared in the title. Since its discovery in 1979,the roles of p53 in By now,a steadily increasing number of laboratories tumourigenesis have changed remarkably. The ability worldwide pursue the idea of a mutant p53 gain of of the initially cloned TP53 genes to immortalize certain function (GOF). Significantly,the European Commis- cell types and to cooperate with other oncogenes in sion (EC) has funded a small research consortium in its cellular transformation classified the TP53 gene as framework programme five,and a considerably larger a cellular oncogene. Consistent with this view was the one in its framework programme six,for research on observation that the levels of p53 protein in tumour cells mutant p53 GOF and its clinical implications,empha- were significantly higher than p53 levels in normal cells. sizing the growing impact of mutant p53 as an At that time,however, TP53 was ‘just another’ important determinant in human tumour development oncogene,and a relatively inefficient one,too,with and progression. completely unknown function. Consequently,p53 at- In the present issue of Oncogene Reviews,I have tracted only a few researchers outside the SV40 field, tried to collect the views of scientists closely involved where p53 was discovered as a cellular protein in in and pioneering the research on mutant p53,most complex with the major transforming protein of this of them being partners in the EC programme. Their small DNA tumour virus,the SV40 T-antigen. As we all views address aspects on the role of mutant p53 in know,the story changed dramatically when in 1988 it tumorigenesis that currently are considered being was discovered that the TP53 genes hitherto used in the most important ones. However,little as we know different laboratories all coded for mutant p53 proteins, about mutant p53 biology,novel discoveries might and that the corresponding wild-type TP53 gene quickly change the field or at least the emphasis suppressed,rather than further cellular transformation. on certain topics. The issue starts with a critical Together with data appearing from the mutational reflection on certain aspects of wild-type and mutant analysis of the TP53 gene in human tumours,the TP53 p53 by Soussi. His review makes a good start,as gene turned from an oncogene into a tumour suppressor it points out several pitfalls in interpreting mutant gene (see e.g. the Introduction by Weisz et al.,this issue, (and wild-type) p53 data that have led to dogmas for further details on the story). Meanwhile,p53 has that might be wrong or at least overinterpreted. His developed into one of the most intensely studied article is followed by a review of data and their proteins in human tumours,with about 3600 citations implications deduced from the analysis of a large in PubMed each year. number of human cancers with TP53 gene mutations, Although most studies on p53 address the multitude compiled in the IARC TP53 database (http:// of functions associated with wild-type p53 as a tumour www-p53.iarc.fr/). From the wealth of information suppressor,the story of mutant p53 as an oncogenic contained therein,Petitjean and colleagues extract protein still goes on,although discussed controversially. that the mutational status of the TP53 gene is critically Since the seminal findings by Finlay et al. (1988) that important in influencing the tumour phenotype. point mutations in the wild-type TP53 gene activate the However,no clear picture has emerged so far concerning gene for cooperation with an activated ras gene in the postulated GOF of mutant p53,as loss of wild-type cellular transformation,research on the hypothesis that p53 function appears to be what matters most. This mutant p53 is not just an inactivated tumour suppressor, is a somewhat disturbing finding for the concept of a but displays oncogenic activities on its own,has mutant p53 GOF. However,considering the complexity developed into an important section of p53 biology. of the postulated interactions of mutant p53 with The term ‘gain of function’ coined for summarizing the many cellular pathways as detailed in the later chapters then unknown oncogenic activities of mutant p53 first of this issue,it may well be that the complexity of appeared in a Science article by Halevy et al. (1990) and human cancers,both in their genetics and in their physiology,obscures overt GOF effects of mutant p53. Such an interpretation is favoured by the analysis Correspondence: Dr W Deppert,Heinrich-Pette-Institut fu ¨ r Experi- mentelle,Virologie und Immunologie,Tumor Virology,Martinistrasse of a human cancer with a better known aetiology 52,Hamburg 20251,Germany. and pathogenesis. In their review on TPp53 mutations E-mail: [email protected] and hepatocellular carcinoma,Hussain and colleagues Mutant p53: from guardian to fallen angel W Deppert 2143 describe the aetiology and pathogenesis of liver there is ample evidence that mutant p53 proteins cancers. Different from most other human cancers,the bind to DNA both in vitro and in vivo,with the aetiology of a subset of liver cancers,namely those binding being determined by the structure of the DNA prevailing in southeast Asia,is quite well understood. presented in a non-B conformation (reviewed in Kim The major risk factors in this area are hepatitis B virus and Deppert,2004). Such binding can lead to the (HBV) infections and aflatoxin B1 exposure. Thus transcriptional activation or repression of genes playing the causative agents are known,and the cascade important roles in establishing the malignant phenotype of the many genetic and epigenetic changes underlying of tumour cells. Weisz and colleagues review some tumour development and progression has at least important and well-studied examples that possibly mark been partially unravelled. Concerning TP53 mutations, the beginning in unravelling mutant p53 transcriptomes. the action of aflatoxin B1 is especially intriguing, However,as the number of genes transcriptionally as it always leads to a specific mutation in the TP53 regulated by mutant p53 increases continuously,it gene that leads to the expression of a 249Ser mutant p53. remains a challenging task to understand at the For this particular mutant p53,a GOF could be molecular level the mode of transcriptional activation demonstrated in in vitro experiments when introduced or repression mediated by the direct binding of mutant into p53-null liver carcinoma cells,and the cooperation p53 to genomic DNA. of this mutant p53 with HBV in liver carcinogenesis The evidence for mutant p53 as an oncogenic argues for a GOF by the 249Ser mutant p53 also in vivo. transcription factor is also reviewed by Strano and Clearly,however,the unequivocal demonstration of a colleagues. Their emphasis is on the observation that mutant p53 GOF in human tumours remains an mutant p53,aside from binding directly to DNA,can be important challenge. targeted to DNA indirectly via its interaction with other The notion that a defined genetic environment transcription factors,such as Ets-1,SP-1 and NF-Y. is better suited to unravel the GOF of mutant p53 is This group made the seminal finding that mutant strongly supported using mouse models. Iwakuma p53 bound to the transcription factor NF-Y under and Lozano summarize data obtained with knock-in conditions of genotoxic stress recruits chromatin mice carrying mutant TP53 genes. Such mice provide remodelling factors that activate and augment transcrip- important information on the wild-type p53 functions tion by NF-Y,demonstrating an intimate connection lost when the TP53 gene is partially or completely of mutant p53 with chromatin structure (Di Agostino inactivated,and also clearly demonstrate a mutant et al.,2006). Although the binding of mutant p53 to, p53 GOF,at least for proteins corresponding to human for example NF-Y is mediated by the p53 C-terminus, hot spot mutant proteins. Interestingly,the effects another interaction important for mutant p53 GOF of mutant TP53 genes in knock-in mice are mouses is the interaction of certain mutant p53 proteins with train-dependent,lending further credit to the idea raised the p53 family members p63/p73 via their respective above that the genetic background plays an important core domains,thereby negatively regulating the role in determining the roles of mutant p53 in proapoptotic functions of p63/p73. As discussed in the tumorigenesis. review by Li and Prives,this special interaction possibly What is the molecular basis for mutant p53 GOF? represents an important mutant p53 GOF in tumour Currently there seems to be a consensus that the major development as well as in the response of tumours to molecular function of mutant p53 is modulating the genotoxic stress. transcriptome of the tumour cell. Several different Central to our understanding of mutant p53 function mechanisms,possibly all used by mutant p53 proteins, is a detailed knowledge of the structure of wild-type are discussed in the following chapters. Central to the p53 and of what discerns wild-type and mutant p53 transcriptional activities of mutant p53 are its interac- proteins structurally. This important issue is addressed tions with chromatin and DNA,as introduced and in the review by Joerger and Fersht and reveals discussed in the review by Kim and Deppert (2004). The a remarkable structural heterogeneity of different implication is that interactions of mutant p53 proteins mutant p53 proteins,with important functional implica- with DNA are complex and may result in different tions. One implication with possible clinical implications mechanisms of transcriptional modulation. The mole- is that the structure of a given mutant p53 protein cularly best understood mode of transcriptional modu- will determine whether or not it can be re-activated lation by mutant p53 derives from the sequence-specific by small molecules to perform wild-type functions. DNA-binding activity of wild-type p53,as reviewed by Selinova and Wiman address this forward-looking Menendez and colleagues. Considering the intricate topic in their review. They show that mutant p53 regulatory network of the wild-type p53 transcriptome, rescue might be a promising therapeutic strategy and it is apparent that an altered specificity of binding to that novel,p53-based anticancer drugs can be deve- response elements,as observed for many mutant p53 loped. A successful introduction of such drugs into proteins in yeast-based p53 transcription assays,will clinical practice would be an enormous step forward profoundly influence and disturb the p53 master for the p53 field as a whole,justifying the huge regulatory network. efforts made worldwide in understanding the complex Although so far no linear DNA sequence motif has biology of the wild-type and mutant p53 functional been defined as a mutant p53-specific response element, networks.

Oncogene Mutant p53: from guardian to fallen angel W Deppert 2144 References

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