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Transcription Regulation by Mutant P53 Oncogene (2007) 26, 2202–2211 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW Transcription regulation by mutant p53 L Weisz, M Oren and V Rotter Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel In addition to the loss of wild-type p53 activity, a high suggests the existence of a strong selection for mutant percentage of tumor cells accumulate mutant p53 protein p53 overexpression in carcinogenesis, making the isoforms.Whereas the hallmark of the wild-type p53 is its investigation of its contribution to malignant processes tumor suppressor activities, tumor-associated mutant p53 crucial to understand better cancer and facilitate the proteins acquire novel functions enabling them to promote development of novel therapies. a large spectrum of cancer phenotypes.During the last years, it became clear that tumor-associated mutant p53 proteins are not only distinct from the wild-type p53, but Discovery of TP53 mutations in cancer they also represent a heterogeneous population of proteins with a variety of structure–function features.One of the p53 was first discovered in 1979 as an SV40-binding major mechanisms underlying mutant p53 gain of function protein (Chang et al., 1979; Kress et al., 1979; Lane and is the ability to regulate gene expression.Although a large Crawford, 1979; Linzer and Levine, 1979). The first number of specific target genes were identified, the reports indicated that the protein is prevalent in many molecular basis for this regulation is not fully elucidated. transformed cell lines, unlike normal cells where its This review describes the present knowledge about the expression is low to undetectable (DeLeo et al., 1979; transcriptional activities of mutant p53 and the mechan- Kress et al., 1979; Lane and Crawford, 1979; Linzer isms that might underlie its target gene specificity. et al., 1979; Rotter et al., 1980). This difference was Oncogene (2007) 26, 2202–2211. doi:10.1038/sj.onc.1210294 ascribed to the short half-life of p53 in normal cells and its stabilization in transformed cells (Oren et al., 1982). Keywords: mutant p53; gain of function; transcription; The tight positive correlation between p53 protein levels mechanism and transformation seemingly supported the notion of p53 as a transformation-associated protein or a proto- oncogene. This notion was further enhanced by subsequent studies that demonstrated upregulation of p53 expression in proliferating cells (Milner and Milner, Introduction 1981; Mercer et al., 1982; Milner, 1984; Reich and Levine, 1984). The p53 tumor suppressor serves as one of the major The molecular cloning of the TP53 gene (Zakut- cellular barriers against cancer development. Indeed, in Houri et al., 1983; Zakut-Houri et al., 1985) further almost all human cancers, the p53 pathway is impaired enabled the understanding of p53 structure and func- (Vogelstein et al., 2000). About half of the tumors tion. Exogenous expression of cloned TP53 was shown sustain mutations in the TP53 gene itself, whereas the to immortalize cells (Jenkins et al., 1984) and endow other half maintain a wild-type TP53 gene but acquire them with overt tumorigenic potential in mice (Wolf other genetic or epigenetic alterations that compromise et al., 1984; Eliyahu et al., 1985). Furthermore, cloned the p53 response. Most of the mutations within the TP53 could co-operate with Ha-ras to transform normal TP53 gene are missense mutations, resulting in the rat embryonic fibroblasts (Eliyahu et al., 1984; Parada expression of full-length mutant p53 (mutp53) proteins et al., 1984). All this evidence strengthened the notion (Hussain and Harris, 1998). This is quite unique as most that p53 possesses cancer-promoting properties. In other tumor suppressor genes are frequently inactivated parallel, it was reported that p53 proteins from by frame shift or nonsense mutations leading to either transformed and normal cells react differently with a production of truncated proteins or complete elimina- set of conformation-specific monoclonal antibodies tion of the corresponding gene products. Moreover, the (Milner and Cook, 1986), suggesting that the conforma- mutated p53 proteins become highly expressed in human tion of p53 might vary between normal and cancer cells, cancers, reaching levels far above those observed in perhaps accounting for the different protein stabilities. normal cells expressing wild-type p53 (wtp53). This However, elucidation of the sequence of mouse wt TP53 gene (Eliyahu et al., 1988; Finlay et al., 1988) Correspondence: Dr V Rotter, Department of Molecular Cell Biology, revealed that all the experiments discussed above, Weizmann Institute of Science, Rehovot 76100, Israel. utilizing cloned TP53, actually employed mutant var- E-mail: [email protected] iants of the protein. Such mutations endowed the Translation regulation by mutant p53 L Weisz et al 2203 protein with the abilities to immortalize cells, bind the DBD mutations compromise the ability of p53 to bind heat shock protein hsp70 and react with specific with high affinity to specific DNA sequences. Structu- monoclonal antibodies (Jenkins et al., 1985; Hinds rally, these mutations can be roughly divided into two et al., 1987; Ben David et al., 1988; Finlay et al., main classes: those that alter amino acid residues 1988). Thus, the available data did not provide any responsible for forming sequence-specific contacts with answer to the question whether authentic wtp53 indeed DNA (DNA contact mutants), and those that disrupt contributes positively to cancer. In parallel, evidence the global conformation of p53 (conformational or was obtained showing inactivation of the TP53 gene in structural mutants). The diversity of TP53 mutations transformed lymphoid cell lines induced by Ab-MuLV found in human cancer is intriguing, and may be virus. Likewise, TP53 gene inactivation and frequent explained by the flexibility of the DNA-binding core rearrangements were shown in mouse spleen tumors domain of p53, which can adopt at least five thermo- induced by the Friend erythroleukaemia virus (Mowat dynamic states (Bullock and Fersht, 2001). Function- et al., 1985; Chow et al., 1987; Munroe et al., 1988), ally, TP53 mutations result in loss of wtp53 tumor strongly suggesting that p53 inactivation, rather than suppressor activities, acquisition of an ability to excessive p53 activation, might promote transformation. suppress the function of the remaining wild-type TP53 The suggestion was confirmed when it was shown that allele via a dominant-negative mechanism, and at least the wtp53 protein is devoid of any transforming activity, in some cases also wtp53-independent gain of oncogenic and that such activity is exhibited only by plasmids function. Different mutations may vary with regard to encoding mutant, tumor-derived forms of p53 (Eliyahu their contribution to each of these three outcomes. et al., 1988; Finlay et al., 1988; Hinds et al., 1989). Generally, the more the mutation disrupts the original Importantly, it could be demonstrated that wtp53 not wild-type conformation, the less wtp53 activity will be only failed to transform cells, but actually actively retained, and the more likely it is that new oncogenic suppressed oncogene-mediated transformation (Eliyahu functions will prevail. Furthermore, as wtp53 has very et al., 1989; Finlay et al., 1989). This, along with data diverse activities, including some that may help cell emanating from the study of human tumor specimens survival through increased capacity to cope with stress, (Baker et al., 1989), firmly established wtp53 as a bona mutants that retain only those particular activities of fide tumor suppressor rather than an oncogene. wtp53 while having lost the other ones may also contribute Equipped with this novel understanding, many to cancer. The heterogeneity of p53 mutants is discussed experiments performed during the first years of p53 extensively in a review by Soussi and Lozano (2005). research could be reinterpreted, establishing the basis During the process of carcinogenesis, TP53 mutations for elucidation of the various roles of p53 in carcinogen- mostly arise sporadically in one allele, resulting in cells esis. Several cancer-related processes could be discerned: expressing both wild-type and mutp53, where the latter (1) p53 loss of function – wtp53 can exert growth- might suppress the tumor suppressor activities of the inhibitory effects on cancer cells, effects that are former by oligomerizing with it through the C-terminal abrogated when the TP53 gene undergoes mutations tetramerization domain (reviewed in Sigal and Rotter, or complete loss in the course of tumor development. (2) 2000). Eventually, in the course of tumor progression, Mutp53 Dominant-negative function – Mutp53 expres- the remaining wt TP53 allele is often lost (mostly by sion in cells harboring wtp53 may enable the mutant deletion), further enhancing tumorigenesis. Analysis of protein to inactivate the endogenous wtp53 and over- Li-Fraumeni syndrome family members, heterozygous come its tumor-suppressive functions, therefore promot- for germline TP53 mutations, as well as mouse models ing tumorigenesis. (3) Mutp53 gain of function (GOF) trying to mimic this syndrome, have revealed a high – expression of mutp53 in cells lacking wtp53 enhances propensity to develop a broad spectrum of tumors at an their tumorigenic potential (Wolf et al., 1984), whereas its early age. Most of the arising tumors were found to downregulation (e.g. by antisense
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