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25 Years of p53 Research

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The First Twenty-Five Years of p53 Research

Harlan Robins; Gabriela Alexe; Sandra Harris; A. J. Levine

During the 1960s, the field of cancer research lacked clear direction. Several facts appeared to be well-established and correct, but the relationships among these observations were not apparent. Fifty years of research had demonstrated that viruses with both DNA and RNA genomes could cause cancer in animals. Over the next 45 years six new viruses were to be discovered that were able to initiate cancers in humans (Epstein-Barr Virus, Human T-Cell Leukemia Virus, Hepatitis B and C Viruses, Kaposi Sarcoma Virus and the Papilloma Viruses) (McKinnel et al., 1998). It was equally clear from the perspective of the 1960s that certain chemicals, when applied to animals, were able to initiate cancers (Yamagawa et al., 1918). Chemical carcinogenesis was a field both separate and distinct (both in the experiments one did and the experimentalists who did them) from viral carcinogenesis and very few scientists thought to find a common ground between concepts generated in each field. Thirdly, the study of mouse genetics demonstrated that some cancers were clearly inherited and these observations confirmed many prior publications that suggested a role for cancer causing genes in humans and other animals (DeOme, 1965). Finally epidemiologists, studying a variety of important variables that predispose humans to developing cancers, had made the very striking observation that the rates of cancer incidence increase exponentially with age and begin to rise dramatically by the fifth and sixth decade of life (Miller, 1991). While these four observations were all accepted facts the relationship between these concepts was not clear and researchers who studied viruses hardly ever discussed chemicals and those who thought about genes and viruses didn’t know what to make of aging as an important variable. Literally researchers from each of these fields, virology, chemical carcinogenesis, genetics and epidemiology never got together to discuss these issues.

Palabras clave: Tumor Antigen; Nonsense Mutation; Silent Mutation; IARC TP53 Database; SV40 Large Tumor Antigen.

Pp. 1-25

Regulation of p53 DNA Binding

Kristine McKinney; Carol Prives

p53 is one of the most frequently mutated genes in human cancers and, as a result, is also one of the most well-studied genes in the history of cancer research. Although many functions have been ascribed to p53 over the years, one of the first activities to be characterized was the ability to bind DNA sequence-specifically through its central domain (reviewed in Vogelstein & Kinzler, 1992). This domain, also frequently referred to as “the core” due to its protease resistance (Bargonetti et al., 1993; Pavletich et al., 1993), contains the most evolutionarily conserved sequences of the protein, both between p53 proteins from different species and between the different p53 family members, p63 and p73 (reviewed in Yang et al., 2002). This region is also the most frequently mutated domain of p53 in the major forms of human cancer (Hainaut & Hollstein, 2000; Olivier et al., 2002). Consequently much research has focused on understanding this crucial ability as well as its regulation. Indeed, the regulation of p53 DNA binding has generated much debate recently, specifically with regard to the role of the C-terminus.

Palabras clave: Core Domain; Tetramerization Domain.

Pp. 27-51

20 Years of DNA Damage Signaling to p53

Kevin G. McLure; Michael B. Kastan

The short history of p53 contains an overwhelming number of facts and hypotheses, presenting the challenge of integrating diverse and sometimes mutually exclusive ideas into a coherent picture. It is important to make a distinction between p53 tumor suppressor activity, the mechanism of which remains speculative, and p53 responses to DNA damage, which are well characterized. Because critical steps in tumorigenesis involve genomic fixation of DNA damage-induced mutations, it seems reasonable to assume that DNA damage signaling to p53 would activate p53 tumor suppressor activity. However, this has not been demonstrated, and p53 tumor suppressor activity may not require the acute p53 response to DNA damage (Komarov et al., 1999). Nonetheless, the genotoxic chemicals and ionizing radiation that are clinically used to treat human cancer indisputably activate wild type p53.

Palabras clave: Ataxia Telangiectasia; Ataxia Telangiectasia.

Pp. 53-71

Gatekeepers of the Guardian: p53 Regulation by Post-Translational Modification, MDM2 and MDMX

Geoffrey M. Wahl; Jayne M. Stommel; Kurt Krummel; Mark Wade

Happy 25th Anniversary p53 ! Since this is such a special occasion, I (GW) thought of explaining how fate brought p53 and me together. It was a snowy day in Utah when Arnie Levine came to the University of Utah in 1976 to present a lecture on genetic approaches to differentiation of teratocarcinoma cells. My graduate work with Mario Capecchi (starting at Harvard and continuing at the University of Utah) led me to appreciate the potential power of genetics in cancer research. I therefore arranged to visit Arnie’s lab to learn more about his research program. We discussed many topics, but not about how the large transforming protein (T antigen) of SV40 (SV40TAg) interacted with a putative ~54kDα cellular protein (Linzer and Levine, 1979).

Palabras clave: Nuclear Export; Nuclear Export Signal; Unstressed Cell; Basal Transcription Machinery; Global Genomic Repair.

Pp. 73-113

Regulation of the p53 Response by Cellular Growth and Survival Factors

Lauren Brown; Samuel Benchimol

In response to abnormal proliferative signals and many forms of cellular stress including DNA damage and ribonucleotide depletion, p53 induces cells to undergo a transient arrest in G1 that is believed to allow time for repair of damaged DNA before the initiation of S phase. Failure to arrest in G1 can lead to chromosome aberrations and genomic instability. Activated p53 can also eliminate cells from the proliferative population through mechanisms that involve prolonged arrest in G1 (as seen during telomereinitiated replicative senescence and stress/DNA damage-induced premature senescence) and apoptosis (Levine, 1997; Oren, 2003; Vogelstein et al., 2000). The elimination of damaged, stressed or abnormally proliferating cells by p53 is considered to be the principal means by which p53 mediates tumour suppression (Symonds et al., 1994; Schmitt et al., 2002). Inappropriate or prolonged activation of p53 in normal tissues, however, can lead to tissue damage and has been associated with multiple sclerosis (Wosik et al., 2003), neurodegenerative disorders and exacerbation of ischemic damage from stroke or cardiac arrest (Mattson et al., 2001; Komarova and Gudkov, 2001). Accordingly, the regulation of p53 function is important for the maintenance of tissue homeostasis.

Palabras clave: Curr Biol; Erythroid Differentiation; Defective Neural Tube; Growth Factor Withdrawal; Negative Regulatory Loop.

Pp. 115-140

P53, Cell Cycle Arrest and Apoptosis

Shulin Wang; Wafik S. El-Deiry

The p53 gene, first described in 1979, was the first tumor suppressor gene to be identified (Lane and Crawford, 1979; Linzer and Levine, 1979). It was originally identified as an oncogene- a cell cycle accelerator, but subsequent studies ten years after its discovery confirmed it to be a tumor suppressor gene that is highly mutated in a wide variety of tumors (Baker et al., 1990; Finlay et al., 1989). In about half of the tumors, p53 is inactivated directly as a result of mutations in the p53 gene. In many others, it is inactivated indirectly through binding to viral proteins, or as a result of alterations in the genes whose products interact with p53 or transmit information to or from p53. The tumor suppressor protein p53 acts as a major node in a complex signaling pathway that evolved to sense a broad range of cellular stresses such as DNA damage, oncogene activation, nucleotide depletion, and hypoxia (Figure 1). In the absence of cellular stress, the p53 protein is expressed at low steady-state levels and exerts little, if any, effect on cell fate.

Palabras clave: Cell Cycle Arrest; Death Receptor; Cell Death Differ; Trail Sensitivity; Autoregulatory Feedback Loop.

Pp. 141-163

P53 Has a Direct Pro-apoptotic Action at the Mitochondria

Ute M. Moll

The basis for p53’s striking apoptotic and tumor suppressive potency lies in its pleiotropism that includes transcription-dependent and –independent functions. p53 kills cells predominantly via the mitochondrial death pathway rather than the death receptor pathway (Schuler et al. 2001). p53 can mediate apoptosis by transcriptional activation of pro-apoptotic genes like the BH3- only proteins Noxa and Puma, Bax, p53 AIP1, Apaf-1, DRAL and PERP, and by transcriptional repression of Bcl2 and IAPs. For Noxa, Puma and PIDD, downregulation decreases - but does not abolish – the extent of death after stress. Of note, induction of these target gene products show variable kinetics, with some being delayed in their response (over 24 h), e.g. Bax and p53AIP1 (Attardi et al. 2000; Nakano et al. 2001). Analysis of p53-regulated global gene expression shows that the type, strength and kinetics of the target gene profiles depends on p53 levels, stress type and cell type (Zhao et al. 2000). This indicates that only individual genes will be chosen from the complex spectrum of potentially inducible genes to mediate a specific p53 response in a given physiological situation.

Palabras clave: Outer Mitochondrial Membrane; Death Receptor Pathway; Death Stimulus; BH123 Protein; Mitochondrial Death Pathway.

Pp. 165-181

Manipulating the p53 Gene in the Mouse: Organismal Functions of a Prototype Tumor Suppressor

Lawrence A. Donehower; Dora Bocangel; Melissa Dumble; Guillermina Lozano

The early discoveries elucidating p53 function were based on cell culture experiments. Most of our fundamental knowledge of the role of p53 in cell signaling, stress response, cell cycle control, and apoptosis are a result of these in vitro studies (Giaccia and Kastan, 1998; Ko and Prives, 1996; Levine, 1997; Vogelstein et al., 2000). However, a greater depth of understanding was facilitated by the advent first of transgenic mouse methodologies and then by embryonic stem (ES) cell-based genetic manipulations. The sequencing of the mouse genome (www.ensembl.org and www.myscience.appliedbiosystems.com) has greatly simplified and accelerated the generation of null alleles. Methods have been developed to generate single nucleotide substitutions in the germline of mice, and importantly, to generate somatic mutations in genes to study somatic inactivation as occurs in most human cancers. The availability of whole genome analysis at the RNA expression level (arrays) and at the genomic level (array CGH) provides another level of analysis that is sure to provide insights into the molecular changes that lead to the initiation, progression, and maintenance of the tumor phenotype.

Palabras clave: Malignant Peripheral Nerve Sheath Tumor; Tumor Spectrum.

Pp. 183-207

P53, P63, and P73: Internecine Relations?

Frank McKeon; Annie Yang

The discoveries of p63 and p73 as genes related to the vaunted tumor suppressor p53 launched questions that remain largely unanswered, and fuel controversy and debate. Do these homologs behave like p53? Do they also act in tumor suppression? What were their origins – spin-offs of an ancestral p53 gene, or, in fact, predecessors of this famed ‘guardian of the genome’? In vivo studies clearly reveal distinct physiological roles for p53, p63, and p73. But do these belie cooperative or antagonistic interactions within the p53 gene family?

Palabras clave: Proliferative Potential; Epithelial Stem Cell; Cortical Lamination; Sterile Alpha Motif; INK4A Locus.

Pp. 209-222

P73, P63 and Mutant P53: Members of Protein Complexs Floating in Cancer Cells

Olimpia Monti; Alexander Damalas; Sabrina Strano; Giovanni Blandino

Approximately half of human tumors bear p53 mutations (Hollestein et al., 1997). The most prevalent type consists of missense mutations that are frequently accompanied by loss of the remaining wild-type p53 (wt-p53) allele (Hainaut et al., 1997; Levine, 1997). The major site of the p53 mutations is the highly conserved DNA binding core domain (Hussain et al., 1998; Prives et al., 1999). Thus, mutant p53 (mt-p53) proteins are unable to specifically bind DNA and to activate specific wt-p53 target genes. Unlike wt-p53, whose half-life is short, mutant p53 proteins are quite stable and abundantly present in cancer cells. One certain outcome of p53 mutations is the loss of wild type activities such as growth arrest, apoptosis, and differentiation (Michalovitz et al., 1990; Yonish-Rouach et al., 1991; Soddu et al., 1996; Almog et al., 1997). However, at variance with other tumor suppressor genes, cells with p53 mutations maintain expression of the fulllength protein. This may suggest that, at least certain mutant forms of p53 can gain additional functions through which actively contribute to cancer progression (Prives et al., 1999; Sigal et al., 2000; Strano et al., 2001; Bullock et al., 2001). Such evidence is provided by several in vitro and in vivo studies (Haley et al., 1990; Dittmer et al., 1993; Gualberto et al., 1998; Frazier et al., 1998; Li et al., 1998; Blandino et al., 1999; Aas et al., 1996; Irwin et al., 2003; Strano et al., 2003)

Palabras clave: Core Domain; Specific Target Gene; Conformational Mutant; Target Transcriptional Activation; Colony Suppression Assay.

Pp. 223-232

P53: Gatekeeper, Caretaker or Both?

Carlos P. Rubbi; Jo Milner

Soon after the discovery of the p53 protein in 1979, the p53 gene was found to be mutated in about half of all human cancers. However, mainly due to the fact that the normally low levels of the p53 protein can be elevated in many cancers, it took some time to realise that p53 was in fact a tumour suppressor gene (Finlay et al., 1989; Levine et al., 1991). This concept was further consolidated by the discovery that the familial cancer predisposition known as Li-Fraumeni syndrome1 is linked to germ-line mutation of the p53 gene (for a review see Varley et al., 1997), and by the clear tumour propensity shown by p53 knock-out mice (for a review see Venkatachalam and Donehower, 1998).

Palabras clave: Cell Cycle Arrest; Nucleotide Excision Repair; Base Excision Repair; Xeroderma Pigmentosum; Double Strand Break.

Pp. 233-253

Analysis of p53 Gene Alterations in Cancer: A Critical View

Thierry Soussi

“Guardian of the genome” (Lane, 1992), “Death star” (Vousden, 2000), “Good and bad cop” (Sharpless and DePinho, 2002), “An acrobat in tumorigenesis” (Moll and Schramm, 1998), are just a few of the names that have been attributed to the p53 gene over recent years. However, the cameras (and funding) were certainly not present at the time of the discovery of p53 in 1979 (Crawford, 1983). It was only when the first alterations of the p53 gene in human cancers were discovered 10 years later, in 1989, that p53 started to become really popular, with the title of “molecule of the year” attributed by Science , in 1993 (Harris, 1993). This title was certainly justified, as the observation that more than one half of human cancers expressed a mutant p53 raised extensive clinical possibilities both for diagnosis and treatment.

Palabras clave: Cervical Cancer; TP53 Mutation; Inflammatory Breast Cancer; Critical View; Adrenal Cortical Carcinoma.

Pp. 255-292

Patterns of TP53 Mutations in Human Cancer: Interplay Between Mutagenesis, DNA Repair and Selection

Hong Shi; Florence Le Calvez; Magali Olivier; Pierre Hainaut

Somatic mutations are the cornerstone of cancer (Hanahan et al. 2000). The development of cancer involves the contributions of many heritable genetic events as well as of a large number of epigenetic changes, but what makes the turning point between untransformed and transformed cell irreversible is the acquisition of targeted, somatic mutations, conferring to cells a selective advantage for clonal proliferation. These mutations can occur in many different genes, but only a handful of them are frequently mutated in a wide variety of human cancers. They include genes of the RAS family (mainly KRAS ), BRAF1, APC,α–Catenin, p16/INK4a, PTEN and TP53 . After over 20 years of research on mutation detection in cancers, TP53 remains the world champion of somatic mutations, with over 70 % of all the mutations described so far in human cancers (Hainaut et al. 2000).

Palabras clave: Polycyclic Aromatic Hydrocarbon; TP53 Mutation; Mutation Pattern; Cyclobutane Pyrimidine Dimer; Human Gene Mutation Database.

Pp. 293-319

Prognostic and Predictive Value of TP53 Mutations in Human Cancer

Magali Olivier; Pierre Hainaut; Anne-Lise Børresen-Dale

Finding reliable molecular markers for early diagnosis, prognosis and prediction of response to treatment is a major challenge for cancer management. A marker of prognosis provides information on the risk of relapse and death independently of treatment, whereas a predicitve marker provides information on the potential benefit of a specific treatment (Lonning, 2003). An early diagnostic marker helps to identify lesions at high risk of malignant transformation. Clinical stage, tumor size and morphological grade are the most reliable factors of prognosis. Among numerous molecular markers that have been tested most recently, only a few are used in clinical practice. In breast cancer for example, estrogen and progesterone receptors are used routinely as predictive markers for tumor response to anti-hormone therapy. However, about 30 % of patients with positive receptor status (expected to benefit from anti-hormone treatment) will face a therapeutic failure, showing the limitations of these markers.

Palabras clave: TP53 Mutation; TP53 Gene; TP53 Mutation Status; TP53 Mutation Analysis; IARC TP53 Database.

Pp. 321-338

P53 Links Tumor Development to Cancer Therapy

Michael T. Hemann; Scott W. Lowe

Anti-cancer therapy operates on the assumption that the genetic pathways disrupted during tumorigenesis are distinct from those that mediate drug sensitivity. The main objective of this therapy is to present tumor cells with obstacles unrelated to the process of cellular transformation or to exploit vulnerabilities created by tumor development, such as uncontrolled DNA synthesis, checkpoint abnormalities, or an addiction to an oncogenic signal. Cytotoxic therapies, for example, rely on the introduction of DNA damage or the inhibition of chromosome segregation. These lesions, when introduced at high levels, elicit a DNA damage response presumably distinct from any encountered during the early stages of tumor development.

Palabras clave: Histiocytic Sarcoma; Choroid Plexus Carcinoma; Semin Cancer Biol; Bcl2 Tumor; Oncogenic Insult.

Pp. 339-351

Novel p53-Based Therapies: Strategies and Future Prospects

Sonia Lain; David Lane

Introducing functional p53 into tumours using adenoviral vectors is leading to success in clinical trials (Edelman et al., 2003; http;//www.introgen.com/infotp.html; http;//www.sibiono.com) and p53 gene therapy gained regulatory approval in China in 2003 where it has been on sale since January 2004. Renewed optimism around the use of p53 gene therapy and increased understanding of p53 function suggest that many more potent and selective variants of p53 may be developed. Reactivating mutant p53 or exploiting specific properties of tumour cells carrying mutations in p53 is a greater challenge. As described elsewhere in this book, tackling this problem has led to a variety of very exciting discoveries. Here we have focused on the current approaches to activate p53 in those cancers that retain wild type p53.

Palabras clave: HDAC Inhibitor; Nuclear Export; Suberoylanilide Hydroxamic Acid; Mdm2 Level; Mdm2 Binding.

Pp. 353-376

Wild Type p53 Conformation, Structural Consequences of p53 Mutations and Mechanisms of Mutant p53 Rescue

Andreas C. Joerger; Assaf Friedler; Alan R. Fersht

The tumor suppressor p53 is a transcription factor that is at the center of a network of interactions that affect the cell cycle and apoptosis (Vogelstein et al. 2000; Ryan et al. 2001). The protein is induced by a variety of stresses that include oncogene activation and DNA damage caused by chemotherapy and radiotherapy. On induction, it activates a variety of genes whose products lead to G1 and G2 cell cycle arrest and apoptosis (Vogelstein et al. 2000; Ryan et al. 2001). It is such an effective tumor suppressor that it is inactivated in virtually all cancers; in about 50 % of cancers p53 is directly inactivated by mutation and in the remainder its activity is lost by perturbations of its associated pathways and interactions (Hainaut and Hollstein 2000). Reactivating mutant p53 is an important target in the development of novel therapies for cancer (Lane and Lain 2002; Lane and Hupp 2003). To understand how p53 is inactivated, it is necessary to understand its structure and how it responds to mutation. Such knowledge will provide a basis for the rational design of novel therapeutics that may reverse the effects of mutation. In this chapter, we survey the structure of the protein, the effects of mutation and how they may be reversed.

Palabras clave: Core Domain; Chemical Shift Change; Suppressor Mutation; Chemical Chaperone; Quadruple Mutant.

Pp. 377-397

Mutant p53 Reactivation as a Novel Strategy for Cancer Therapy

Galina Selivanova; Vladimir J. N. Bykov; Klas G. Wiman

Inactivation of the p53 tumor suppressor by point mutation occurs in a large fraction of human tumors, including almost all tumor types (see p53 Mutation database at http://www.iarc.fr/p53). A majority of p53 mutations are missense mutations that give rise to the expression of mutant p53 proteins with one amino acid substitution. This pattern of mutation stands in sharp contrast to those of most other tumor suppressor genes, e.g. the Rb and p16 genes, which are frequently inactivated by homozygous deletion, smaller deletions or promoter methylation that either results in complete lack of expression of the protein, or expression of a truncated unstable protein. This suggests that p53 mutation not only serves to inactivate p53 but that expression of mutant p53 itself may provide a selective advantage to tumor cells and promote tumor growth. First, point mutant p53 proteins may act in a dominant negative manner, i.e. inhibit the activity of a wild type allele present in the same cell through hetero-oligomerization that forces wild type p53 to adopt a mutant conformation (Milner and Medcalf 1991). In addition, mutant p53 proteins may have acquired novel activites that could support the growth of tumors. These so called gain-of-function (GOF) activities of mutant p53 could involve promiscuous DNA binding and illegitimate activation of target genes, such as the c-Myc oncogene, the multidrug resistance gene (MDR1), VEGF, and the dUTPase gene ((Frazier et al. 1998; Pugacheva et al. 2002; Tsang et al. 2003); www.iarc.fr/p53), whose activation could contribute to tumor development. Moreover, mutant p53 could enhance cell cycle progression and/or cell survival through novel interactions with cellular protein partners, as examplified by the binding of mutant p53 to p73 and other p53 family members (Di Como et al. 1999; Marin and Kaelin 2000; Strano et al. 2002; Monti et al. 2003; Strano and Blandino 2003).

Palabras clave: Core Domain; National Cancer Institute Database; Transcription Activation Function; Mutant Conformation; dUTPase Gene.

Pp. 399-419

Novel Approaches to p53-Based Therapy: ONYX-015

Frank McCormick

Cancer is caused by gain of function of proteins involved in proliferation and survival, and loss of function of proteins that regulate these processes (Hanahan and Weinberg, 2000). Strategies for treating cancer generally involve development of small molecules that block hyperactive enzymes, or take advantage of abnormal expression of protein targets on the surface of cancer cells. Developing therapies based on loss of function of tumor suppressors presents novel challenges. Loss of the protein phosphates PTEN and loss of the G1/S checkpoint protein pRB occurs frequently in cancer, and offers a number of potential drug targets. Loss of PTEN leads to hyperactivation of downstream enzymes such as AKT and mTOR (McCormick, 2004) whereas loss of pRB leads to hyper-activation of the transcription factor E2F, and increased expression of numerous potential targets, some of which have already been exploited for cancer therapy (dihydrofolate reductase and thymidylate synthase, for example, are the targets of methotrexate and 5-fluorouracil, respectively). Loss of p53, on the other hand, does not appear to offer any direct targets for intervention: in contrast to PTEN and pRB, p53 is a positive regulatory protein, whose targets are obviously lost rather than hyper-activated in cancer cells.

Palabras clave: Cancer Gene Therapy; Oncolytic Adenovirus; Mdm2 Activity; Primary Human Epithelial Cell; Positive Regulatory Protein.

Pp. 421-429

p53 as Seen by an Outsider

George Klein

Has the p53-field made a major impact on cancer research? Indeed it has. From its earliest beginnings, cancer research has been looking for “the” fundamental change in cancer cells, the ultimate common denominator. The idea that such a change must exist, was, if not abandoned, substantially mollified by the increasing realization, from the late 1950s, that cancer development is a multistep process, based on the individual reassortment of several unit characteristics (Foulds, 1958) or, as we now say, phenotypic traits.

Palabras clave: Mouse Mammary Tumor Virus; Epigenetic Inactivation; Lung Adenoma; Apoptotic Sensitivity; Colorectal Adenoma Risk.

Pp. 431-438

Información

Tipo: libros

ISBN impreso

978-1-4020-2920-2

ISBN electrónico

978-1-4020-2922-6

Editor responsable

Springer Nature

País de edición

Reino Unido

Fecha de publicación