1: Cell Cycle. 2007 Jul;6(13):1570-3. Epub 2007 May 22.


Gain of function of p53 cancer mutants in disrupting critical DNA damage response pathways.

Song H, Xu Y.

Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093, USA.

Loss of the tumor suppression activity of p53 is required for the progression of most human cancers. In this context, p53 gene is somatically mutated in about half of all human cancers; in the rest human cancers, p53 is mostly inactivated due to the disruption of pathways important for its activation. Most p53 cancer mutations are missense mutations within the core domain, leading to the expression of full-length mutant p53 protein. The expression of p53 mutants is usually correlated with the poor prognosis of the cancer patients. Accumulating evidence has indicated that p53 cancer mutants not only lose the tumor suppression activity of WT p53, but also gain novel oncogenic activities to promote tumorigenesis and drug resistance. Therefore, to improve current cancer therapy, it is critical to elucidate the gain-of-functions of p53 cancer mutants. By analyzing the humanized p53 mutant knock-in mouse models, we have identified a new gain of function of the common p53 cancer mutants in inducing genetic instability by disrupting ATM-mediated cellular responses to DNA double-stranded break (DSB) damage. Considering that some current cancer therapies such as radiotherapy kills the cancer cells by inducing DSBs in their genome DNA, our findings will have important implications on the treatment of human cancers that express common p53 mutants.

Publication Types:
Research Support, U.S. Gov't, Non-P.H.S.
Review

PMID: 17598983 [PubMed - indexed for MEDLINE]

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2: Oncogene. 2007 Apr 2;26(15):2226-42.


Structure-function-rescue: the diverse nature of common p53 cancer mutants.

Joerger AC, Fersht AR.

Centre for Protein Engineering, Medical Research Council Centre, Cambridge, UK. acj2@mrc-lmb.cam.ac.uk

The tumor suppressor protein p53 is inactivated by mutation in about half of all human cancers. Most mutations are located in the DNA-binding domain of the protein. It is, therefore, important to understand the structure of p53 and how it responds to mutation, so as to predict the phenotypic response and cancer prognosis. In this review, we present recent structural and systematic functional data that elucidate the molecular basis of how p53 is inactivated by different types of cancer mutation. Intriguingly, common cancer mutants exhibit a variety of distinct local structural changes, while the overall structural scaffold is largely preserved. The diverse structural and energetic response to mutation determines: (i) the folding state of a particular mutant under physiological conditions; (ii) its affinity for the various p53 target DNA sequences; and (iii) its protein-protein interactions both within the p53 tetramer and with a multitude of regulatory proteins. Further, the structural details of individual mutants provide the basis for the design of specific and generic drugs for cancer therapy purposes. In combination with studies on second-site suppressor mutations, it appears that some mutants are ideal rescue candidates, whereas for others simple pharmacological rescue by small molecule drugs may not be successful.

Publication Types:
Review

PMID: 17401432 [PubMed - indexed for MEDLINE]

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3: Oncogene. 2007 Apr 2;26(15):2220-5.


Are interactions with p63 and p73 involved in mutant p53 gain of oncogenic function?

Li Y, Prives C.

Department of Biological Sciences, Columbia University, New York, NY 10027, USA.

Although still controversial, the presence of mutant p53 in cancer cells may result in more aggressive tumors and correspondingly worse outcomes. The means by which mutant p53 exerts such pro-oncogenic activity are currently under extensive investigation and different models have been proposed. We focus here on a proposed mechanism by which a subset of tumor-derived p53 mutants physically interact with p53 family members, p63 and p73, and negatively regulate their proapoptotic function. Both cell-based assays and knock-in mice expressing mutant forms of p53 support this model. As more than half of human tumors harbor mutant forms of p53 protein, approaches aimed at disrupting the pathological interactions among p53 family members might be of clinical value.

Publication Types:
Review

PMID: 17401431 [PubMed - indexed for MEDLINE]

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4: Head Neck. 2007 Mar;29(3):272-84.


Restoration of wild-type p53 function in human cancer: relevance for tumor therapy.

Bossi G, Sacchi A.

Department of Experimental Oncology, Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, Rome, Italy.

BACKGROUND: In the majority of human cancers, the tumor suppressor activity of p53 is impaired because of mutational events or interactions with other proteins (ie, MDM2). The loss of p53 function is responsible for increased aggressiveness of cancers, while tumor chemoresistance and radioresistance are dependent upon the expression of mutant p53 proteins. METHODS: Review of the literature indicates that p53 acts primarily as a transcription factor whose function is subject to a complex and diverse array of covalent post-translational modifications that markedly influence the expression of p53 target genes responsible for cellular responses such as growth arrest, senescence, or apoptosis. The ability of p53 to induce apoptosis in cancer cells is believed essential for cancer therapy. RESULTS: Numerous data indicate that p53 dependent apoptosis is a relevant factor in determining the efficacy of anticancer treatments. Thus, the development of new strategies for restoration of p53 function in human tumors is considered an important issue. Two main approaches for restoration of p53 function have been pursued that impact anticancer treatments: (a) de novo expression of wild-type p53 (wt-p53) through gene therapy and (b) identification of small molecules reactivating wt-p53 function. CONCLUSIONS: The extensive body of knowledge acquired has identified manipulations of p53 signaling as a relevant issue for successful therapies. In this context, the recognition of p53 status in cancer cells is significant and would help considerably in the selection of an appropriate therapeutic approach. p53 manipulations for cancer therapy have revealed the need for specificity of p53 activation and ability to spare body tissues. Furthermore, the promising results obtained by using molecules competent to reactivate wt-p53 functions in cancer cells provide the basis for the design of new molecules with lower side effects and higher anti-tumor efficiency. The reexpression and reactivation of p53 protein in human cancer cells would increase tumor susceptibility to radiation or chemotherapy enhancing the efficacy of standard therapeutic protocols.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 17230559 [PubMed - indexed for MEDLINE]

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5: Head Neck. 2007 May;29(5):488-96.


Mutant p53 proteins: between loss and gain of function.

Strano S, Dell'Orso S, Mongiovi AM, Monti O, Lapi E, Di Agostino S, Fontemaggi G, Blandino G.

Department of Experimental Oncology, Regina Elena Cancer Institute, 00158 Rome, Italy.

Cancer might result from both the aberrant activation of genes, whose physiological tuning is essential for the life of a normal cell, and the inactivation of tumor suppressor genes, whose main job is to preserve the integrity of cell genome. Among the latter, p53 is considered a key tumor suppressor gene that is inactivated mainly by missense mutations in half of human cancers. It is becoming increasingly clear that the resulting mutant p53 proteins gain oncogenic properties favoring the insurgence, the maintenance, and the spreading of malignant tumors. In this review, we mainly discuss the molecular mechanisms underlying gain of function of human tumor-derived p53 mutants, their impact on the chemoresistance and the prognosis of human tumors, with a special focus on head and neck cancers, and the perspectives of treating tumors through the manipulation of mutant p53 proteins. (c) 2006 Wiley Periodicals, Inc.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 17123310 [PubMed - indexed for MEDLINE]

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6: Cell Death Differ. 2006 Jun;13(6):984-93.


Some p53-binding proteins that can function as arbiters of life and death.

Braithwaite AW, Del Sal G, Lu X.

Department of Pathology, School of Medicine, University of Otago, Dunedin, New Zealand. antony.braithwaite@stonebow.otago.ac.nz

Four sets of p53-binding proteins are discussed in this review. These are the E2F family, the ASPP family, Y-box-binding protein YB1, and the prolyl isomerase Pin1. Each appears to play a role in the decision by p53 to induce an arrest of cell proliferation or apoptosis and they may also be independent markers of cancer. Their activities appear to be linked with the cell cycle and they may also interact with each other. In this review, the properties of each protein class are discussed as well as how they affect p53 functions. A model is proposed as to how their activities might be coordinated.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 16575404 [PubMed - indexed for MEDLINE]

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7: Cell Death Differ. 2006 Jun;13(6):902-8.


Dissecting p53 tumor suppressor function in vivo through the analysis of genetically modified mice.

Johnson TM, Attardi LD.

Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University Medical School, Stanford, CA, USA.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Review

PMID: 16557272 [PubMed - indexed for MEDLINE]

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8: Biol Cell. 2006 Mar;98(3):141-52.


Control of cell migration: a tumour suppressor function for p53?

Roger L, Gadea G, Roux P.

Centre de Recherche en Biochimie Macromoléculaire, CNRS FRE 2593, IFR 24, 1919 route de Mende, F-34293 Montpellier cedex 5, France.

Much remains to be learned about how cancer cells acquire the property of migration, a prerequisite for invasiveness and metastasis. Loss of p53 functions is assumed to be a crucial step in the development of many types of cancers, leading to dysregulation of cell cycle checkpoint controls and apoptosis. However, emerging evidence shows that the contribution of the tumour suppressor p53 to the control of tumorigenesis is not restricted to its well-known anti-proliferative activities, but is extended to other stages of cancer development, i.e. the modulation of cell migration. This interesting alternative function has been proposed in light of the effect of p53 on specific features of migrating cells, including cell spreading, establishment of cell polarization and the production of protrusions. The effects of p53 on cell motility are largely mediated through the regulation of Rho signalling, thereby controlling actin cytoskeletal organization. These recent studies connect the regulation of proliferation to the control of cell migration and define a new concept of p53 function as a tumour suppressor gene, suggesting that p53 might be involved in tumour invasion and metastasis. This review focuses on emerging data concerning the properties of p53 that contribute to its atypical role in the regulation of cell migration.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 16480340 [PubMed - indexed for MEDLINE]

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9: Front Biosci. 2005 Jan 1;10:919-30. Print 2005 Jan 1.


Setting the stage for transformation: HTLV-1 Tax inhibition of p53 function.

Pise-Masison CA, Brady JN.

Virus Tumor Biology Section, Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 41 Room B201, 9000 Rockville Pike, Bethesda, MD 20892, USA.

Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia and tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). Although the precise mechanism of HTLV-1 oncogenesis remains unclear, the pathogenesis has been linked to the pleiotropic activity of the viral transcriptional activator protein Tax. Tax has been shown to regulate viral and cellular gene expression and to functionally interfere with proteins involved in cell-cycle progression and DNA repair. This review will concentrate on the ability of Tax to promote cellular proliferation through activation of the NF-kappaB pathway while inhibiting the cell-cycle checkpoint and apoptotic function of the tumor suppressor gene p53.

Publication Types:
Review

PMID: 15569630 [PubMed - indexed for MEDLINE]

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10: Carcinogenesis. 2004 Sep;25(9):1551-7. Epub 2004 Jul 1.


Remodelling chromatin on a global scale: a novel protective function of p53.

Allison SJ, Milner J.

YCR P53 Research Group, Department of Biology, University of York, York YO10 5DD, UK. sja13@york.ac.uk

The tumour suppressor p53 has an essential role in maintaining the genomic integrity of the mammalian cell. This is achieved in part through its function as a transcription factor enabling it to induce either growth arrest or apoptosis in response to cellular stress. Changes in gene expression commonly require localized chromatin remodelling and p53 is known to interact in vivo with a variety of transcriptional co-activators and co-repressors with intrinsic histone modifying activities. Here we examine the links between p53 and chromatin structures associated with (i) transcriptional regulation of gene expression, (ii) with DNA repair as part of the process of nucleotide excision repair and (iii) with histone modifications which impact upon chromosomal condensation and ploidy.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 15231688 [PubMed - indexed for MEDLINE]

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11: Acta Dermatovenerol Croat. 2003 Dec;11(4):225-30. Related Articles


Protein p53--structure, function, and possible therapeutic implications.

Batinac T, Gruber F, Lipozencić J, Zamolo-Koncar G, Stasić A, Brajac I.

Department of Dermatovenerology, Rijeka University Hospital Center, Rijeka, Croatia. tanjabatinac@net.hr

Cell cycle is driven by a number of positive and negative regulatory phosphorylation and dephosphorylation events that ultimately influence the activity of transcription factors. Normal skin architecture depends on the regulation mechanisms of cell proliferation and differentiation and on apoptosis. Complex interaction of different factors in the regulation of these mechanisms, aimed at maintaining constant desquamation, is often changed in skin diseases. The main difference between normal cells and tumor cells results from discrete changes in specific genes important for cell proliferation control mechanisms and tissue homeostasis. These genes are mainly proto-oncogenes or tumor-suppressor genes, and their mutation could play a role in cell hyperproliferation and carcinogenesis. Tumor-suppressor genes normally function as a physiological barrier against clonal expansion or mutation accumulation in the genome. They also control and arrest growth of the cells that hyperproliferate due to oncogene activity. Alteration or DNA damage in tumor-suppressor genes and oncogenes are considered key events in human carcinogenesis. Tumor-suppressor protein p53 is an important transcription factor, which plays a central role in the cell cycle regulation mechanisms and cell proliferation control, and its inactivation is considered a key event in human carcinogenesis. The role of p53 protein in the cell cycle, high proportion of tumors with mutated p53 gene, and accumulation of significant amount of knowledge on molecular biology of this protein make this molecule especially attractive for development of new therapeutic approaches. Main strategies for development of new antineoplastic therapies are based on "wild-type" p53 protein acting as a tumor suppressor, selective apoptosis inductor, and a protein able to arrest cell cycle.

Publication Types:
Review

PMID: 14670223 [PubMed - indexed for MEDLINE]

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12: Folia Biol (Praha). 2003;49(1):1-8.


What we currently know about the structure and function of the p53 homologue - p73 protein: facts, hypotheses and expectations.

Cesková P, Valík D, Vojtĕsek B.

Department of Experimental Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 12630662 [PubMed - indexed for MEDLINE]

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13: Cell Cycle. 2002 Nov-Dec;1(6):362-8.


Therapeutic exploitation of checkpoint defects in cancer cells lacking p53 function.

Dixon H, Norbury CJ.

Cancer Research UK Molecular Oncology Laboratory, University of Oxford Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford UK.

Cytotoxic agents form the basis of most cancer therapies. These agents primarily affect rapidly proliferating cells, so their use incurs morbidity associated with damage to tissues such as bone marrow and gastrointestinal mucosa. Clinical outcome would be improved if it were possible to develop therapeutics with more specific activity against p53-deficient cancers, which account for over 50% of all cases. p53 deficiency alters the cellular response to DNA damage in that it leaves cells with attenuated DNA damage checkpoint controls and a reduced propensity for apoptotic cell death. Thus, the DNA repair capacity of these cells is reduced but survival is increased. This promotes genomic instability and contributes to the resistance of p53-deficient cells to cytotoxic agents. Disabling the residual G(2) checkpoint function of p53-deficient cells may favour cell death following DNA damage. Several potential strategies for G(2) checkpoint abrogation show promise for the specific sensitization of cancer cells. Here we detail how the G(2) DNA damage checkpoint is influenced by p53 status and how the loss of p53 function in cancer cells can be exploited to enhance the cytotoxicity of anti-cancer agents.

Publication Types:
Review

PMID: 12548006 [PubMed - indexed for MEDLINE]

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14: Nat Rev Cancer. 2001 Oct;1(1):68-76.


Rescuing the function of mutant p53.

Bullock AN, Fersht AR.

Department of Biochemistry, University of Washington, Seattle, USA.

One protein--p53--plays nemesis to most cancers by condemning damaged cells to death or quarantining them for repair. But the activity of p53 relies on its intact native conformation, which can be lost following mutation of a single nucleotide. With thousands of such mutations identified in patients, how can a future cancer drug buttress this fragile protein structure and restore the cell's natural defence?

Publication Types:
Review

PMID: 11900253 [PubMed - indexed for MEDLINE]

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15: J Photochem Photobiol B. 2001 Oct;63(1-3):78-83.


Acute response of human skin to solar radiation: regulation and function of the p53 protein.

Decraene D, Agostinis P, Pupe A, de Haes P, Garmyn M.

Department of Dermatology, University of Leuven, Kapucijnenvoer 33, B-3000 Leuven, Belgium.

p53 is a tumor suppressor gene and mutation of p53 is a frequent event in skin cancer. The wild-type p53 encodes for a 53-kD phosphoprotein that plays a pivotal role in regulating cell growth and cell death. The wt-p53 gene is also called "guardian of the genome", for its role in preventing the accumulation of genetic alterations, observed in cancer cells. The wild-type p53 protein plays a central role in the response of the cell to DNA damage. UV, present in sunlight, is one of the most ubiquitously present DNA damage inducing stress conditions to which skin cells are exposed. The wt-p53 protein accumulates in human skin cells in vitro and in human skin in vivo upon UV irradiation. This upregulation mounts a protective response against permanent DNA damage through transactivation of either cell cycle arrest genes and DNA repair genes or genes that mediate the apoptotic response. The molecular events which regulate the activity of the wt-p53 protein activity are only beginning to be described.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 11684454 [PubMed - indexed for MEDLINE]

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16: Gene. 2001 Oct 17;277(1-2):15-30.


The effects of wild-type p53 tumor suppressor activity and mutant p53 gain-of-function on cell growth.

Cadwell C, Zambetti GP.

Department of Biochemistry, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA.

The tumor suppressor p53 plays a central role in the protection against DNA damage and other forms of physiological stress primarily by inducing cell cycle arrest or apoptosis. Mutation of p53, which is the most frequent genetic alteration detected in human cancers, inactivates these growth regulatory functions and causes a loss of tumor suppressor activity. In some cases, mutation also confers tumor-promoting functions, such as the transcriptional activation of genes involved in cell proliferation, cell survival and angiogenesis. Consequently, cells expressing some forms of mutant p53 show enhanced tumorigenic potential with increased resistance to chemotherapy and radiation. Our current understanding of these activities is summarized in this review. By dissecting out mechanistic differences between wild-type and mutant p53 activities, it may be possible to develop therapeutics that restore tumor suppressor function to mutant p53 or that selectively inactivate mutant p53 tumor-promoting functions.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 11602342 [PubMed - indexed for MEDLINE]

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17: Antioxid Redox Signal. 2001 Aug;3(4):611-23.


Zinc binding and redox control of p53 structure and function.

Hainaut P, Mann K.

Group of Molecular Carcinogenesis, International Agency for Research on Cancer, Lyon, France. Hainaut@iarc.fr

The p53 protein is a tumor suppressor often inactivated in cancer, which controls cell proliferation and survival through several coordinated pathways. The p53 protein is induced in response to many forms of cellular stress, genotoxic or not. p53 is a zinc-binding protein containing several reactive cysteines, and its key biochemical property, sequence-specific DNA binding, is dependent upon metal and redox regulation in vitro. In this review, we describe the main features of p53 as a metalloprotein and we discuss how metal binding and oxidation-reduction may affect p53 activity in vivo. In particular, we stress the possible involvement of thioredoxin, Ref-1 (redox factor 1), and metallothionein in the control of p53 protein conformation and activity. Furthermore, we also review the available evidence on the role of p53 as a transactivator or transrepressor of genes involved in the production and control of reactive oxygen intermediates. Overall, these data indicate that p53 lies at the center of a network of complex redox interactions. In this network, p53 can control the timely production of reactive oxygen intermediates (e.g., to initiate apoptosis), but this activity is itself under the control of changes in metal levels and in cellular redox status. This redox sensitivity may be one of the biochemical mechanisms by which p53 acts as a "sensor" of multiple forms of stress.

Publication Types:
Comparative Study
Review

PMID: 11554448 [PubMed - indexed for MEDLINE]

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18: Oncogene. 2001 May 10;20(21):2611-7.


The role of tetramerization in p53 function.

Chène P.

Novartis, K125 420, CH-4002 Basel, Switzerland.

The tumour suppressor gene p53 is extensively studied for its importance in cancer. In its active conformation, p53 is tetrameric and one domain - the tetramerization domain - permits the oligomerization of this protein. Until recently, little attention was given to this domain because, in contrast to the DNA-binding domain, it is not often mutated in cancer. However, various experimental studies have shown evidence that the tetramerization domain is essential for DNA binding, protein-protein interactions, post-translational modifications, and p53 degradation. Moreover, single mutations in the tetramerization domain can inactivate the wild-type protein in a manner similar to that seen with mutations in the DNA-binding domain. Interestingly, the phenotype of several tetramerization domain mutants differs from that observed with DNA-binding domain mutants. In this review, current knowledge about the importance of the tetramerization domain to the function of p53 will be summarized.

Publication Types:
Review

PMID: 11420672 [PubMed - indexed for MEDLINE]

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19: J Cell Biochem Suppl. 2000;Suppl 35:115-22.


Mutant p53: "gain of function" through perturbation of nuclear structure and function?

Deppert W, Göhler T, Koga H, Kim E.

Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität Hamburg, Martinistr.52, D-20251 Hamburg, Germany. deppert@hpi.uni-hamburg.de

Mutant p53 not simply is an inactivated tumor suppressor, as at least some mutant p53 proteins exhibit oncogenic properties. Mutant p53 thus is the most commonly expressed oncogene in human cancer. Accordingly, the expression of mutant p53 in tumors often correlates with bad prognosis, and expression of mutant p53 in p53-negative tumor cells enhances their transformed phenotype. The molecular basis for this "gain of function" is not yet understood. However, the finding that mutant p53 tightly associates with the nuclear matrix in vivo, and with high affinity binds to nuclear matrix attachment region (MAR) DNA in vitro, suggests that these activities are connected and may result in perturbation of nuclear structure and function in tumor cells. MAR-binding of mutant p53 most likely is due to conformation-selective DNA binding by mutant p53, i.e. the specific interaction of a given mutant p53 protein with regulatory or structural genomic DNA elements that are able to adopt specific non-B-DNA conformations. In support to this assumption, human mutant p53 (Gly(245)-->Ser) was shown to bind to repetitive DNA elements in vivo that might be part of MAR elements. This further supports a model according to which mutant p53, by interacting with key structural components of the nucleus, exerts its oncogenic activities through perturbation of nuclear structure and function. J. Cell. Biochem. Suppl. 35:115-122, 2000. Copyright 2001 Wiley-Liss, Inc.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 11389540 [PubMed - indexed for MEDLINE]

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20: Curr Opin Cell Biol. 2001 Jun;13(3):332-7.


Regulation and function of the p53 tumor suppressor protein.

Ryan KM, Phillips AC, Vousden KH.

Regulation of Cell Growth Laboratory, Building 560, Room 22-96, National Cancer Institute at Frederick, Frederick, MD 21702, USA.

Loss of the p53 tumor suppressor pathway contributes to the development of most human cancers. p53 is a nuclear protein that functions as a regulator of transcription. Significant advances have been made recently in our understanding of how p53 function is regulated and the mechanisms by which p53 mediates its effects.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 11343904 [PubMed - indexed for MEDLINE]

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21: Exp Cell Res. 2001 Mar 10;264(1):56-66.


Regulation of p53 function.

Woods DB, Vousden KH.

Regulation of Cell Growth Laboratory, National Cancer Institute, 1050 Boyles Street, Frederick, Maryland 21702-1201, USA.

Publication Types:
Review

PMID: 11237523 [PubMed - indexed for MEDLINE]

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22: Yakugaku Zasshi. 2000 Dec;120(12):1387-94.


[Suppressive effect of protein kinase C inhibitors on tumor cell function via phosphorylation of p53 protein in mice]

[Article in Japanese]

Nakamura K, Shinozuka K, Kunitomo M.

Faculty of Pharmaceutical Sciences, Mukogawa Women's University, 11-68, Koshien Kyuban-cho, Nishinomiya 663-8179, Japan.

We examined the role of protein kinase C (PKC) in the phosphorylation of a p53 protein. Exposure to a protein kinase inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7), increased the phosphorylation of the wild type p53 protein, whereas exposure to a tumor promoter phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), decreased it in vivo after incubation with mouse epidermal JB6 cells for 3 h. Exposure to a cAMP dependent protein kinase (PKA) activator, forskolin, did not decrease the phosphorylation of p53 protein. In the transient transfection/luciferase reporter transactivation assay, H7 slightly increased the mouse double minute (MDM) 2 reporter transactivation activity of the p53 protein after treatment for 24 h, whereas TPA completely blocked it. Exposure to H7 and a specific PKC inhibitor, bisindolylmaleimide (bis), dose-dependently reduced the lung-colonizing potential of highly metastatic B16-F10 mouse melanoma cells in syngeneic mice. These results suggest that the phosphorylation of the wild type p53 protein is inversely related to PKC activation, and also suggest that the phosphorylation of the p53 protein is involved in the function of its transcription factor. The PKC inhibitor may exhibit a potent anti-metastatic effect through the phosphorylation of wild type p53 protein and the activation of its function.

Publication Types:
English Abstract
Review

PMID: 11193387 [PubMed - indexed for MEDLINE]

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23: FASEB J. 2000 Oct;14(13):1901-7.


p53 from complexity to simplicity: mutant p53 stabilization, gain-of-function, and dominant-negative effect.

Blagosklonny MV.

Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. mikhailb@box-m.nih.gov

Increasing the complexity of their models, p53s are stabilized either in order to function (wt p53) or due to the loss of function (mutant p53) with acquiring a mysterious prion-like ability to drive the normal p53 into the abnormal conformation to gain new functions. As already recognized, the loss of trans-activating function leads to a stabilization of mutant p53 because of the disappearance of the p53-inducible proteins, which otherwise directly (Mdm-2) or indirectly (p21) target p53 for degradation. Simplifying further, I will discuss that the loss of function results in a dominant-negative effect and gain-of-function (a dominant-positive effect). Thus, mutant p53 lacking trans-activation function nevertheless may retain the ability to repress transcription due to its competition with numerous transcription factors for their coactivators. When mutant p53 competes with wt p53, the inhibition of the wt p53-dependent transcription is perceived as a dominant-negative effect. Just like trans-repression, a dominant-negative effect requires an excess of p53 and, therefore, a 'dominant'-negative effect is not dominant. Furthermore, the stabilization of an endogenous mt p53 due to the loss of wt functions cannot occur in the presence of the wt p53 allele. Given the inability of mutant p53 to accumulate in the presence of wt p53, a dominant-negative effect does not naturally occur and, not surprisingly, heterozygous mt/wt cells are rare. The detection of a dominant-negative effect simply indicates that mutant p53 indeed has lost its function. Last, since mutant p53 loses some or most but not all activities and accumulates in the absence of wt allele, gain-of-function can be considered as an exaggeration of the remaining functions. Applications to cancer therapy are discussed. -Blagosklonny, M. V. p53 from complexity to simplicity: mutant p53 stabilization, gain-of-function, and dominant-negative effect.

Publication Types:
Review

PMID: 11023974 [PubMed - indexed for MEDLINE]

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24: Clin Cancer Res. 2000 Jun;6(6):2138-45.


Gain-of-function mutations in the tumor suppressor gene p53.

van Oijen MG, Slootweg PJ.

Department of Pathology, University Medical Center Utrecht, The Netherlands.

The tumor suppressor protein p53 is a multifunctional transcription factor involved in the control of cell cycle progression, DNA integrity, and cell survival. p53 is mutated in half of all tumors and has a wide spectrum of mutation types. p53 mutants show different degrees of dominance over coexpressed wild-type p53, and loss of the wild-type p53 allele has been observed frequently. Several p53 mutants can exert oncogenic functions beyond their negative domination over the wild-type p53 tumor suppressor functions. These so-called gain-of-function effects, such as enhancement of tumorigenicity and therapy resistance, were investigated in p53-null cells. The possible mechanisms by which p53 mutants exert their gain-of-function effects are reviewed. The existence of functional gains of certain p53 mutants has important ramifications for tumor prognosis and cancer therapies.

Publication Types:
Review

PMID: 10873062 [PubMed - indexed for MEDLINE]

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25: Histol Histopathol. 2000 Apr;15(2):551-6.


Gain of function properties of mutant p53 proteins at the mitotic spindle cell cycle checkpoint.

Hixon ML, Flores A, Wagner M, Gualberto A.

Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.

Mutations in the p53 tumor suppressor gene locus predispose human cells to chromosomal instability. This is due in part to interference of mutant p53 proteins with the activity of the mitotic spindle and postmitotic cell cycle checkpoints. Recent data demonstrates that wild type p53 is required for postmitotic checkpoint activity, but plays no role at the mitotic spindle checkpoint. Likewise, structural dominant p53 mutants demonstrate gain-of-function properties at the mitotic spindle checkpoint and dominant negative properties at the postmitotic checkpoint. At mitosis, mutant p53 proteins interfere with the control of the metaphase-to-anaphase progression by up-regulating the expression of CKs1, a protein that mediates activatory phosphorylation of the anaphase promoting complex (APC) by Cdc2. Cells that carry mutant p53 proteins overexpress CKs1 and are unable to sustain APC inactivation and mitotic arrest. Thus, mutant p53 gain-of-function at mitosis constitutes a key component to the origin of chromosomal instability in mutant p53 cells.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 10809376 [PubMed - indexed for MEDLINE]

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26: Front Biosci. 2000 Apr 1;5:D424-37.


Tumor suppressor p53: regulation and function.

Somasundaram K.

Laboratory of Molecular Oncology and Cell Cycle Regulation University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

The p53 protein is a transcription factor involved in maintaining genomic integrity by controlling cell cycle progression and cell survival. Mutations in p53 are the most frequently seen genetic alterations in human cancer. The function of p53 is critical to the way many cancer treatments kill cells because radiotherapy and chemotherapy act in part by triggering programmed cell death in response to DNA damage. Consequently, tumors which bear p53 mutations, are often difficult to treat and their prognosis is poor. Since the underlying feature of tumors with p53 mutations is the absence of functional p53, gene replacement therapy with wild-type p53 gene is being considered as an approach for treating a variety of cancers. In recent years, more information has been obtained regarding various pathways leading to the activation of p53, particularly those involving post-translational modifications of p53. Several new target genes of p53 have been identified. This review will summarize current knowledge on the structure, mechanism of activation and effectors of p53 function.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 10762600 [PubMed - indexed for MEDLINE]

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27: Trends Cell Biol. 2000 May;10(5):197-202.


Regulation and function of the p53-related proteins: same family, different rules.

Lohrum MA, Vousden KH.

Regulation of Cell Growth Laboratory, NCI-FCRDC, Frederick, MD 21702-1201, USA.

The tumour-suppressor protein p53 has recently been shown to belong to a family that includes two structurally related proteins, p63 and p73. Although all three proteins share similar transcriptional functions and the ability to induce apoptosis, each of them appears to play a distinct role in development and tumour suppression. In order for cell division to occur, the antiproliferative activities of these proteins must be tightly controlled, and exciting advances have been made in our understanding of the pathways involved in regulating p53 activity.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 10754563 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

28: Adv Exp Med Biol. 1999;472:89-100.


Regulation of p53 function in normal and malignant cells.

Tortora V, Bontempo P, Verdicchio M, Armetta I, Abbondanza C, Schiavone EM, Nola E, Puca GA, Molinari AM.

Institute of General Pathology and Oncology, Second University of Naples, Italy.

Publication Types:
Review

PMID: 10736619 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

29: Biochemistry (Mosc). 2000 Jan;65(1):28-40.


Function of the p53 gene: choice between life and death.

Chumakov PM.

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 117984, Russia. chumakov@imb.ac.ru

Gene p53 is a central component of a system that eliminates pathologically damaged cells from an organism. Multiple signal pathways monitor the state of a cell and when damage or a fault is found that could cause heritable changes, p53 protein is activated to either coordinate the repair process or induce cell suicide. Thus, the p53 gene acts as a supreme judge that decides the fate of cells and guarantees their social behavior. Loss of the p53 gene results in uncontrolled accumulation of genetic damage causing failure of control by the organism, malignant cell growth, and death of the organism.

Publication Types:
Review

PMID: 10702638 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

30: Cell Death Differ. 1999 Dec;6(12):1169-73.


Comment in:
Cell Death Differ. 1999 Dec;6(12):1143.

Structure and function in the p53 family.

Arrowsmith CH.

Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, 610 University Ave., Toronto, Ontario, Canada M5G 2M9. carrow@oci.utoronto.ca

The recent discovery of several p53 homologs has uncovered a p53 superfamily of transcription factors that can trigger cell cycle arrest and apoptosis. The challenge now is to understand the similarities and differences between family members especially in terms of their regulation and potential for physical or genetic interactions with one another. This review summarizes recent progress in understanding the structure-function relationship within the p53 family. The new family members, p63 and p73, have an additional conserved domain at their C-termini which may have a regulatory function. The structure of this domain (a SAM domain) suggests that it is a protein-protein interaction module that may be involved in developmental processes. The oligomerization domains of p53 family members, while conserved in sequence and three-dimensional structure do not interact appreciably with other family members, but do mediate interactions between the multiple splice variants from an individual gene.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 10637432 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

31: Proc Nutr Soc. 1999 Aug;58(3):565-71.


Metal ions as regulators of the conformation and function of the tumour suppressor protein p53: implications for carcinogenesis.

Méplan C, Verhaegh G, Richard MJ, Hainaut P.

International Agency for Research on Cancer, Lyon, France.

The p53 protein is a multi-function nuclear factor that is activated in response to multiple forms of stress and controls the proliferation, survival, DNA repair and differentiation of cells exposed to potentially genotoxic DNA damage. Loss of p53 function by mutation is a frequent event in human cancer, and is thought to result in the capacity of cells to acquire and accumulate oncogenic mutations during the progression of neoplasia. The p53 protein is a metal-binding transcription factor that is inactivated by metal chelation and by oxidation in vitro. In intact cells, p53 protein activity is crucially dependent on the availability of Zn ions and is impaired by exposure to Cd, a metal which readily substitutes for Zn in a number of transcription factors. Inactivation by Cd suppresses the p53-dependent responses to DNA damage. Overall, these findings indicate that regulation by metals plays an important role in the control of p53, and that perturbation of this control may explain the carcinogenic potential of several metal compounds.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 10604188 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

32: Tanpakushitsu Kakusan Koso. 1999 Nov;44(15 Suppl):2507-10.


[The activation and function of p53 in cellular response to environmental stress]

[Article in Japanese]

Yamamoto K.

Department of Molecular Pathology, Kanazawa University, Japan. kyamamot@kenroku.kanazawa-u.ac.jp

Publication Types:
Review

PMID: 10586708 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

33: Exp Cell Res. 1999 Dec 15;253(2):315-24.


Accumulating active p53 in the nucleus by inhibition of nuclear export: a novel strategy to promote the p53 tumor suppressor function.

Laín S, Xirodimas D, Lane DP.

Department of Biochemistry, University of Dundee, Dundee, Scotland, DD1 5EH, United Kingdom. slain@bad.dundee.ac.uk

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 10585254 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

34: Biol Chem. 1999 Jul-Aug;380(7-8):879-87.


Mutant p53: gain-of-function oncoproteins and wild-type p53 inactivators.

Roemer K.

Department of Virology, University of Saarland Medical School, Homburg/Saar, Germany.

Cancers frequently express mutant forms of the p53 transcription factor and tumor suppressor. Early observations indicated that mutant p53 can enhance the malignancy of tumor cells and immortalize primary cells. Immortalization is also frequently observed in primary cell cultures upon loss of wild-type (wt) p53, and since p53 acts as a tetramer and mutant p53 can hetero-oligomerize with the wild type, a significant number of effects are assigned to mutant p53 acting as a dominant-negative protein. Dominance depends on the ratio of the proteins as well as on the position of the mutated amino acid residue. Mutations that alter the tertiary structure can give rise to proteins capable of forcing upon wt p53 a non-wild-type conformation, and hetero-tetrameric complexes with altered conformation are impaired for DNA binding. Mutations that affect DNA contact sites compromise DNA binding in dependence on the affinity of the hetero-tetrameric complex for a p53 recognition motif. In addition to dominance, mutant p53 can exert oncogenic functions independently of the inactivation of wt p53. Such gain-of-function manifests itself in the enhancement of tumorigenicity, of metastatic potential, and of survival and therapy resistance of wt p53-null tumor cells. The significance of dominant-negative function and gain-of-function for the various cancer phenotypes, for prognosis and for the success of therapy are currently unclear and subject of study.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 10494837 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

35: Cell Mol Life Sci. 1999 Jan;55(1):88-95.


Regulation of p53 protein function through alterations in protein-folding pathways.

Hupp TR.

Dundee Cancer Research Institute, Department of Molecular Oncology, University of Dundee, Scotland, UK.

The tumour suppressor protein p53 is a stress-activated transcription factor whose activity is required for regulating the cellular response to stress and damage. The biochemical activity of p53 as a transcription factor can be regulated by partner proteins affecting stability, nuclear transport, signalling pathways modulating phosphorylation and interactions with components of the transcriptional machinery. The key structural determinants of p53 protein that drive sequence-specific DNA binding include the core specific DNA-binding domain and the tetramerization domain. Flanking these domains are more evolutionarily divergent carboxy- and amino-terminal regulatory motifs that further modulate tetramerization and sequence-specific transactivation. This review will mainly focus on the mechanisms whereby the tetramerization domain modulates sequence-specific DNA binding and how missense point mutations in p53 protein and the activity of molecular chaperones may lead to unfolding of mutant p53 tetramers in human tumours.

Publication Types:
Review

PMID: 10065154 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

36: Results Probl Cell Differ. 1999;23:145-72.


The p53 tumor suppressor gene: structure, function and mechanism of action.

Choisy-Rossi C, Reisdorf P, Yonish-Rouach E.

Laboratoire de Cancérogenèse Moléculaire, UMR 217 du CNRS/CEA, DRR-DSV, CEA, Fontenay-aux-Roses, France.

Publication Types:
Review

PMID: 9950033 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

37: Oncogene. 1997 Oct 16;15(16):1889-93.


Loss of function and p53 protein stabilization.

Blagosklonny MV.

Medicine Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.

Wild-type (wt) p53 protein is rapidly degraded, has a short half-life and low intracellular levels. Stabilization of wt p53 protein following an appropriate stimulus (for example DNA damage) is a physiological regulation to increase function. In contrast, stabilization of p53 protein in the absence of a stimulus is always a hallmark of loss of function secondary to a mutation, or interaction with viral or cellular oncoproteins. It is generally accepted that stability of p53 protein depends on its intrinsic biochemical properties such as conformation or protein/protein interactions. However, I will discuss evidence that the stability of p53 is not a consequence of its intrinsic properties, but instead is determined by feedback control of its function. In the absence of an appropriate stimulus, a cell needs to keep p53 levels low, since increased levels can lead to apoptosis. To precisely regulate p53 levels, a cell must sense its level; and sensing its transactivating function, is the simplest way to sense p53. Following an appropriate stimulus (for example, DNA damage), the cell senses a state of 'relative' p53 deficiency and adapts by reducing p53 degradation. When the state of p53 deficiency is a consequence of a mutation or interaction with viral oncoproteins, the cell does not sense p53, and again attempts to adapt by reducing p53 degradation. However, in the latter case, the increase in levels does not restore function, and the adaptation continues until degradation of p53 protein is maximally inhibited. In this case, no further inhibition of degradation is possible after DNA-damage or pharmacological inhibition of proteasomes. Thus lack of wt p53 function always results in increased p53 levels and nonregulation.

Publication Types:
Review

PMID: 9365234 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

38: Z Gastroenterol. 1997 Jun;35(6):491-509.


[Tumor suppressor gene p53--function and significance in gastroenterology]

[Article in German]

Schoppmeyer K, Keim V, Mössner J.

Medizinische Klinik II, Universität Leipzig.

The p53 gene is a tumor suppressor gene. The encoded p53 protein directly induces the expression of genes that are involved in cell cycle regulation. p53 was named "guardian of the genome" for its prevention of an otherwise fatal outcome under DNA damaging conditions. Under these conditions p53 inhibits cell cycle progression or induces apoptosis. The p53 protein has been structurally and functionally divided into four domains, two of which are of crucial importance: The sequence specific DNA-binding domain and the aminoterminal transactivation domain. They are both required to trigger the downstream processes following p53 expression. Mutations and inactivation of p53 by oncogenes are frequent events in the development of human neoplasia. That includes gastrointestinal tumors with their mutational spectra reflecting tissue-specific influences of endogenous and exogenous factors in carcinogenesis. Despite considerable progress in molecular biology, clinical applicability of p53 in both diagnostic and therapeutic strategies has not yet been validated.

Publication Types:
English Abstract
Review

PMID: 9281241 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

39: Adv Dermatol. 1997;13:121-66.


The regulation and function of the p53 tumor suppressor.

Mansur CP.

New England Medical and Tufts University, Boston, Massachusetts, USA.

Publication Types:
Review

PMID: 9551143 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

40: J Natl Cancer Inst. 1996 Oct 16;88(20):1442-55.


Structure and function of the p53 tumor suppressor gene: clues for rational cancer therapeutic strategies.

Harris CC.

Laboratory of Human Carcinogenesis, Division of Basic Science, National Cancer Institute, Bethesda, MD 20892-4255, USA.

The p53 tumor suppressor protein is involved in multiple central cellular processes, including transcription, DNA repair, genomic stability, senescence, cell cycle control, and apoptosis. p53 is functionally inactivated by structural mutations, interaction with viral products, and endogenous cellular mechanisms in the majority of human cancers. This functional inactivation can, in some circumstances, produce resistance to DNA-damaging agents commonly used in cancer chemotherapy and radiotherapeutic approaches. Current research is defining the biochemical pathways through which p53 induces cell cycle arrest and apoptosis. Knowledge of these fundamental processes is leading to the identification of molecular targets toward which multimodality cancer therapies, using chemotherapeutic, immunotherapeutic, and gene-therapeutic strategies, can be based.

Publication Types:
Review

PMID: 8841019 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

41: Oncogene. 1996 Apr 4;12(7):1379-85.


New insights into p53 function from structural studies.

Arrowsmith CH, Morin P.

Division of Molecular and Structural Biology, Ontario Cancer Institute, University of Toronto, Canada.

Recent structural analysis of p53 has greatly enhanced our understanding of the biochemical activities of this protein by presenting us with a detailed picture of the chemical groups in the protein that are involved in protein stability, conformation and functional interactions. The current structures form the basis for the design of potential therapeutics which could, for example, revert a DNA-binding mutant back to a DNA-binding competent conformation. The structure of the tet domain forms the basis for designing an active therapeutic p53 with an oligomerization domain which would not cross react with a DNA-binding mutant p53. However, as useful as these structures have been in providing insight into the structure/function relationship for p53, a complete understanding of this protein awaits more detailed information on the full-length protein. In this respect, one of the most useful roles for future structural studies will be to help identify the nature of the conformational transition between latent and active p53, and how it can be modulated.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 8622853 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

42: Nippon Rinsho. 1995 Oct;53 Suppl(Pt 2):82-8.


[Transactivation function of HBV X protein and tumor suppressor gene p53]

[Article in Japanese]

Takada S.

Department of Gene Research, Cancer Institute, JFCR.

Publication Types:
Review

PMID: 12442365 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

43: Ann N Y Acad Sci. 1995 Sep 30;768:111-28.


The spectrum of mutations at the p53 locus. Evidence for tissue-specific mutagenesis, selection of mutant alleles, and a "gain of function" phenotype.

Levine AJ, Wu MC, Chang A, Silver A, Attiyeh EF, Lin J, Epstein CB.

Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, New Jersey 08544-1014, USA.

Publication Types:
Comparative Study
Review

PMID: 8526340 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

44: Orv Hetil. 1995 Aug 27;136(35):1875-83.


[The function of the p53 gene suppressor in carcinogenesis]

[Article in Hungarian]

Sándor J, Ambrus T, Ember I.

Pécsi Orvostudományi Egyetem Népegészségtani Intézet.

The alteration of the p53 gene or protein seems to be the most frequent alteration in the human malignancies. It plays a significant role in the regulation of the physiological cell division. The genetic impairments caused by a series of exogenous or endogenous agents induce the activation of the p53 which results in the G1-S arrest to ensure the opportunity for repair to correct the alteration or in apoptosis when the repair is not able to cope with the mutation. Eventually, the p53 is anticarcinogenic because of its genom guarding function. The investigation of the behavior of this gene and protein is fruitful in solving problems of preventive, diagnostic and therapeutic work.

Publication Types:
English Abstract
Review

PMID: 7675427 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

45: Ann Pathol. 1995;15(3):178-83.


[The tumor suppressor gene p53 (part one). Structure, function and mechanisms of inactivation]

[Article in French]

Martin A.

Service d'Anatomie et de Cytologie Pathologiques de l'hôpital Avicenne, Bobigny.

Publication Types:
Review

PMID: 7639853 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

46: Blood. 1994 Oct 15;84(8):2391-411.


Structure and function of p53 in normal cells and their aberrations in cancer cells: projection on the hematologic cell lineages.

Prokocimer M, Rotter V.

Department of Hematology, Beilinson Hospital, Petach Tikvah, Israel.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 7919359 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

47: Int J Cancer. 1994 Jun 1;57(5):623-7.


The regulation of p53 function: Steiner Award Lecture.

Lane DP.

Cancer Research Campaign Laboratories, University of Dundee, UK.

Publication Types:
Review

PMID: 8194867 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

48: Ann N Y Acad Sci. 1994 May 31;716:265-80; discussion 280-2.


Mechanisms of action of the p53 tumor suppressor and prospects for cancer gene therapy by reconstitution of p53 function.

Roemer K, Friedmann T.

Center for Molecular Genetics, University of California, San Diego 92093-0634.

Publication Types:
Review

PMID: 8024199 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

49: Crit Rev Oncog. 1994;5(1):23-57.


Posttranslational regulation of p53 tumor suppressor protein function.

Maxwell SA, Roth JA.

Department of Thoracic and Cardiovascular Surgery, University of Texas-M.D. Anderson Cancer Center, Houston 77030.

Alteration of the p53 gene by deletion and mutation is the most common denominator yet identified among human cancers (Hollstein et al., 1991; Caron de Fromental and Soussi, 1992). The involvement of the p53 gene in such a broad scope of human cancers warrants further investigation into its mechanism of action in regulating cell growth. The wild-type p53 protein restricts cell growth in the G1 phase of the cell cycle by regulating the transcription of genes and possibly, by influencing DNA replication. Elucidating the cell growth restriction of p53 will require identification and characterization of the genes whose expression is regulated by p53 and the proteins that interact with p53 to regulate its DNA-binding and transactivation functions. A model for the regulation of p53 biochemical function is proposed that extends further and builds on the conformational hypothesis for regulation of p53 function hypothesized by Milner (1991) and Ullrich et al. (1992a). The conformational hypothesis of regulation of p53 function states that the conformation of p53 determines whether it expresses growth-suppressing or growth-promoting biological activity. Mutations observed in human cancer lock p53 in a growth-promoting conformation. We expand the conformational hypothesis in a regulatory model that includes binding proteins, kinases/phosphatases, redox modifier proteins, and homo/hetero-oligomerization, which modulate the tertiary structure of the protein. Different conformational modes of p53 interact differently with initiation complexes at gene promoters and at origins of DNA replication. Each form of p53, depending on its interaction with proteins and gene transcription-initiation complexes, will mediate distinct biological effects on cells ranging from growth suppression to growth promotion. Furthermore, depending on its conformational state, p53 can repress or activate other transcription factors thus indirectly affecting gene regulation. We propose that each cell and tissue type expresses unique quantities and types of p53-binding proteins and modifying enzymes that regulate the interaction of p53 with promoters of genes necessary for control of growth of a specific cell or tissue. It is anticipated that defects in the expression of p53 regulatory proteins are involved in a portion of those tumors expressing normal p53. Defects in the p53 biochemical pathway may thus be even more prevalent in human cancers than is now realized.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 7948107 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

50: Cold Spring Harb Symp Quant Biol. 1994;59:427-34.


Transgenic approaches to the analysis of ras and p53 function in multistage carcinogenesis.

Kemp CJ, Burns PA, Brown K, Nagase H, Balmain A.

CRC Beatson Laboratories, Department of Medical Oncology, University of Glasgow, Bearsden, United Kingdom.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 7587097 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

51: Bioessays. 1993 Nov;15(11):703-7.


Discerning the function of p53 by examining its molecular interactions.

Oliner JD.

Johns Hopkins Oncology Center, Baltimore, MD 21231.

Of the many genes mutated on the road to tumor formation, few have received as much attention as p53. The gene has come to occupy center stage for the simple reason that it is more frequently altered in human tumors than any other known gene, undergoing mutation at a significant rate in almost every tumor type in which it has been studied. This association between p53 mutation and tumorigenesis has spurred a flurry of research attempting to delineate the normal function of p53 and, by extension, the role of p53 mutation in tumor formation. At the cellular level, p53 has been shown to suppress growth. Recent efforts to further discern the function of p53 have centered on the underlying molecular basis for this growth suppression. In particular, research has focused on the identification of cellular molecules (specifically DNA and proteins) with which the p53 protein associates. p53 has now been shown to bind DNA in a sequence-specific manner, and mounting evidence suggests that p53 acts as a transcription factor, perhaps regulating the expression levels of genes involved in the inhibition of cell growth. The logical next step in understanding p53 function involves the resolution of two questions: (1) what are the physiological transcriptional targets of p53, and (2) what cellular proteins regulate or mediate the ability of p53 to modulate transcription? Some initial clues to these puzzles are now emerging, and these form the subject of this review.

Publication Types:
Review

PMID: 8292000 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

52: Cell. 1992 Aug 21;70(4):523-6.


p53 function and dysfunction.

Vogelstein B, Kinzler KW.

Johns Hopkins Oncology Center, Baltimore, Maryland 21231.

Publication Types:
Review

PMID: 1505019 [PubMed - indexed for MEDLINE]

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53: Mutat Res. 1992 Aug;277(2):163-71.


Cellular and molecular advances in elucidating p53 function.

Shay JW, Werbin H, Funk WD, Wright WE.

University of Texas Southwestern Medical Center, Department of Cell Biology and Neurosciences, Dallas 75235-9039.

The finding that in many human tumors there is allelic loss and/or mutations in p53, in combination with recognition that these events may play a role in multi-stage carcinogenesis, has focused considerable interest on this gene. To help keep abreast of this rapidly expanding field, recent experiments on the role and potential regulation of p53 are described: these include discussions of p53 as an anti-proliferative agent, the p53 mutations found in human tumors and tumor cell lines, the conformational states of p53, phosphorylation of p53 by p34cdc2, and signals for the nuclear localization of p53. p53 may act as a transcriptional activator and the specific DNA sequences to which p53 protein binds are also discussed as is the importance of abrogation of p53 function in overcoming cellular senescence.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 1378532 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

54: Bioessays. 1992 Aug;14(8):557-60.


p53 loss of function: implications for the processes of immortalization and tumorigenesis.

Finlay CA.

Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, NJ 08544-1014.

The complex process of cell immortalization and transformation is likely to involve the inactivation of growth regulatory genes. Mutations (deletions, missense mutations) in the p53 gene are the most frequently observed genetic alteration in human tumors, making p53 a candidate for a cellular protein involved in the control of cell growth. Two recent studies have examined the role of p53 in immortalization and tumorigenesis. In the first study, p53 expression was examined in both mortal and immortal chick embryo fibroblasts. All mortal clones expressed p53 but the loss of wild-type p53 expression was observed in every immortal cell line examined. In the second study, a line of mice carrying two null p53 alleles has been created and characterized. Although these mice develop normally, they show a predisposition to develop a variety of neoplasms at an early age (< 6 months). Although it is unclear whether p53 regulates the same, different, or overlapping pathways in the two experimental systems, these data demonstrate that p53 function is critical for the maintenance of normal growth control and support the current classification of p53 as a growth suppressive or tumor suppressor gene.

Publication Types:
Review

PMID: 1365909 [PubMed - indexed for MEDLINE]