1: 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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2: Adv Drug Deliv Rev. 2005 Feb 28;57(4):653-60. Epub 2005 Jan 8.


The role of alpha-helical structure in p53 peptides as a determinant for their mechanism of cell death: necrosis versus apoptosis.

Rosal R, Brandt-Rauf P, Pincus MR, Wang H, Mao Y, Li Y, Fine RL.

Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, 701 West 168th Street rm. 5-531, New York, NY 10032, USA.

Peptides derived from the N-terminal and C-terminal regions of the p53 tumor suppressor protein, linked to the membrane transduction domain of Antennapedia, have both been found to have significant cytotoxic effects selectively in human cancer cells. However, the N-terminal and C-terminal p53 peptides apparently display very different mechanisms for their anticancer effects. These differential effects can be attributed to dissimilar abilities to form distinctive 3-dimensional structures in extracellular-matrix-like aqueous solution that enable unique and selective cancer cell membrane penetration and effect. N-terminally based p53 peptides, with their ability to form distinctive S-shaped helix-loop-helix structures, are able to rapidly disrupt cancer cell membranes via toroidal-like pore formation causing necrosis; conversely, C-terminally based p53 peptides, due to their more random coil configuration, can be transduced across cancer cell membranes and bind to its intracellular target to cause a Fas pathway mechanism of apoptosis.

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

PMID: 15722169 [PubMed - indexed for MEDLINE]

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3: 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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4: 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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5: 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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6: 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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7: 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]

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8: 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]

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9: 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]

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10: 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]

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11: 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]

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12: Biochim Biophys Acta. 1985 Nov 12;823(1):67-78.


The p53 cellular tumor antigen: gene structure, expression and protein properties.

Oren M.

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

PMID: 3902087 [PubMed - indexed for MEDLINE]