p53 Interactions
Published by Anonymous on 2007/9/28 (2612 reads)
1: 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]
--------------------------------------------------------------------------------
2: Oncogene. 2007 Apr 2;26(15):2185-90.
Interactions of mutant p53 with DNA: guilt by association.
Kim E, Deppert W.
Translational Neuro-Oncology Group, Department of Neurosurgery, Georg-August-University of Goettingen, Robert-Koch-Strasse 40, Goettingen, Germany. ella.kim@med.uni-goettingen.de
Since the very early days of p53 research, the gain of oncogenic activities by some mutant p53 proteins had been suspected as an important factor contributing to cancer progression. Considerable progress towards understanding the biology of mutant p53 has been made during the last years, the quintessence being the realization that the impact of mutant p53 proteins on the transcriptome of a tumor cell is much more global than previously thought. The emerging role of mutant p53 proteins in coordinating oncogenic signaling and chromatin modifying activities reveals an until now unsuspected function of these proteins as important modifiers of the oncogenic transcriptional response. Notwithstanding the fact that the sequence-specific DNA binding activity of mutant p53 proteins is impaired, they are still able to associate with specific loci on DNA by utilizing different mechanisms. The ability to associate with DNA appears to be crucial for the master role of mutant p53 proteins in coordinating oncogenic transcriptional responses.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 17401427 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
3: Apoptosis. 2006 May;11(5):659-61.
p53 and Retinoblastoma protein (pRb): a complex network of interactions.
Godefroy N, Lemaire C, Mignotte B, Vayssière JL.
Laboratoire de Génétique et Biologie Cellulaire (CNRS UMR8159), Université de Versailles Saint-Quentin-en-Yvelines, 45 Avenue des Etats-Unis, 78035, Versailles Cedex, France.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16554964 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
4: Cell Death Differ. 2006 Jun;13(6):885-9.
The versatile interactions of p53 with DNA: when flexibility serves specificity.
Kim E, Deppert W.
Neuro-Oncology Research Group, Department of Neurosurgery, University of Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, D-23538 Luebeck, Germany.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16543936 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
5: J Nutr. 2004 Sep;134(9):2482S-2486S.
Diet-gene interactions in p53-deficient mice: insulin-like growth factor-1 as a mechanistic target.
Hursting SD, Lavigne JA, Berrigan D, Donehower LA, Davis BJ, Phang JM, Barrett JC, Perkins SN.
Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. hurstins@mail.nih.gov
Progress in cancer prevention research is being facilitated by the use of animal models displaying specific genetic susceptibilities for cancer, such as mice deficient in one (+/-) or both (-/-) alleles of the p53 tumor suppressor gene. Our lab, which focuses on nutrition (particularly energy balance/obesity) and molecular carcinogenesis, has shown in p53-/- mice that calorie restriction (CR) increases the latency of spontaneous tumor development (mostly lymphomas) approximately 75%, decreases serum insulin-like growth factor (IGF)-1 and leptin levels, and induces apoptosis in immature (lymphoma-susceptible) thymocytes. In heterozygous p53-deficient (p53+/-) mice, CR and a one day/wk fast each significantly delay spontaneous tumor development (a mix of lymphomas, sarcomas, and epithelial tumors) and decreases serum IGF-1 and leptin levels, even when begun late in life. We are presently comparing and combining CR and exercise (treadmill and running wheel) to further elucidate the relationships between energy balance, p53, and tumorigenesis in these models. Furthermore, we have capitalized on the susceptibility of p53+/- mice to chronic, low-dose aromatic amine-induced bladder carcinogenesis to develop a model for evaluating bladder cancer prevention approaches. Using this model, we have established that IGF-1 mediates many of the anti-cancer effects of CR. We are currently conducting oligonucleotide microarray studies to further characterize diet-gene interactions underlying the anti-cancer effects of CR and to determine which of the CR-responsive genes are IGF-1 dependent.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 15333746 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
6: Ann N Y Acad Sci. 2004 Jun;1024:54-71.
Physiological and pathological consequences of the interactions of the p53 tumor suppressor with the glucocorticoid, androgen, and estrogen receptors.
Sengupta S, Wasylyk B.
Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
The p53 tumor suppressor plays a key role in protection from the effects of different physiological stresses (DNA damage, hypoxia, transcriptional defects, etc.), and loss of its activity has dire consequences, such as cancer. Its activity is finely tuned through interactions with other important regulatory circuits in the cell. Recently, striking evidence has emerged for crosstalk with another class of important regulators, the steroid hormone receptors, and in particular the glucocorticoid (GR), androgen (AR), and estrogen (ER) receptors. These receptors are important in maintaining homeostasis in response to internal and external stresses (GR) and in the development, growth, and maintenance of the male and female reproductive systems (AR and ER, respectively). We review how p53 interacts closely with these receptors, to the extent that they share the same E3 ubiquitin ligase, the MDM2 oncoprotein. We discuss the different physiological contexts in which such interactions occur, and also how these interactions have been undermined in various pathological situations. We will describe future areas for research, with special emphasis on GR, and how certain common features, such as cytoplasmic anchoring of p53 by the receptors, may become targets for the development of therapeutic interventions. Given the importance of GR in inflammation, erythropoiesis, and autoimmune diseases, and the importance of AR and ER in prostate and breast cancer (respectively), the studies on p53 interactions with the steroid receptors will be an important domain in the near future.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
Review
PMID: 15265773 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
7: Trends Pharmacol Sci. 2004 Jul;25(7):343-6.
Small-molecule inhibitors of the p53 suppressor HDM2: have protein-protein interactions come of age as drug targets?
Fischer PM, Lane DP.
Cyclacel Limited, James Lindsay Place, Dundee DD1 5JJ, Scotland, UK. pfischer@cyclacel.com
Publication Types:
Review
PMID: 15219971 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
8: Cancer Biol Ther. 2004 Feb;3(2):156-61. Epub 2004 Feb 1.
The functional interactions between the p53 and MAPK signaling pathways.
Wu GS.
Program in Molecular Biology and Human Genetics, Karmanos Cancer Institute, Department of Pathology, Wayne State University School of Medicine, Room E216, The Prentis Building, 110 East Warren Avenue, Detroit, Michigan 48201, USA. wug@karmanos.org
The p53 tumor suppressor protein exerts its growth inhibitory activity by activating and interacting with diverse signaling pathways. As a downstream target, p53 protein is phosphorylated and activated by a number of protein kinases in response to stressful stimuli. As an upstream activator, activated p53 acts as a transcription factor to induce and/or suppress a number of genes whose expression leads to the activation of diverse signaling pathways. p53 protein can also interact with a number of proteins, resulting in an increase or decrease in p53 activity itself. The activation of p53 leads to many outcomes in cells, including cell cycle arrest and apoptosis. It has become clear that the p53 protein can functionally interact with the mitogen-activated protein kinase (MAPK) pathways, including the stress-activated protein kinase [SAPK/c-Jun N-terminal protein kinase (JNK)], the p38 mitogen-activated protein kinase (MAPK), and the extracellular signal related kinase (ERK). Upon exposure to stressful stimuli, MAP kinases phosphorylate and activate p53, leading to p53-mediated cellular responses. Recent studies have suggested a role of p53 as an upstream activator to regulate MAPK signaling via the transcriptional activation of members of the dual specificity phosphatase family. Because both the p53 and MAPK signaling pathways are altered in the majority of human tumors, understanding their functional interaction may provide new insights into the deregulated cell proliferation and survival that is characteristic of cancer.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 14764989 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
9: Biochem Biophys Res Commun. 2003 Dec 5;312(1):109-14.
Bacterial cupredoxin azurin and its interactions with the tumor suppressor protein p53.
Punj V, Das Gupta TK, Chakrabarty AM.
Department of Microbiology and Immunology, University of Illinois, College of Medicine, 835 South Wolcott Avenue, Chicago, IL 60612, USA.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 14630027 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
10: Biochem Cell Biol. 2003 Jun;81(3):141-50.
The complex interactions of p53 with target DNA: we learn as we go.
Kim E, Deppert W.
Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie, Universität Hamburg, Germany.
The most import biological function of the tumor suppressor p53 is that of a sequence-specific transactivator. In response to a variety of cellular stress stimuli, p53 induces the transcription of an ever-increasing number of target genes, leading to growth arrest and repair, or to apoptosis. Long considered as a "latent" DNA binder that requires prior activation by C-terminal modification, recent data provide strong evidence that the DNA binding activity of p53 is strongly dependent on structural features within the target DNA and is latent only if the target DNA lacks a certain structural signal code. In this review we discuss evidence for complex interactions of p53 with DNA, which are strongly dependent on the dynamics of DNA structure, especially in the context of chromatin. We provide a model of how this complexity may serve to achieve selectivity of target gene regulation by p53 and how DNA structure in the context of chromatin may serve to modulate p53 functions.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 12897847 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
11: Methods Mol Med. 2003;74:43-59.
Molecular epidemiology of human cancer risk. Gene-environment interactions and p53 mutation spectrum in human lung cancer.
Vähäkangas K.
Department of Pharmacology and Toxicology, University of Kuopio, Finland.
Molecular epidemiology of cancer risk utilizes knowledge of both the genetic changes in cancer and the current hypothesis of chemical carcinogenesis when selecting possible markers for individual susceptibility, early disease, and biologically significant exposure. Polymorphisms of drug-metabolizing enzymes, especially CYP enzymes, and mutations in the p53 tumor-suppressor gene have been in the center of interest for the past decade. Both have shown promise, CYP polymorphisms as markers for individual susceptibility and p53 mutation spectrum at population level for specific exposure. However, it is probable that very few markers, if any, are sufficient alone. Future challenges for molecular epidemiology in the lung cancer field include pursuing ethically the best performance in applying that knowledge, in addition to the development of reliable and well-validated markers.
Publication Types:
Review
PMID: 12415685 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
12: Acta Oncol. 2001;40(6):739-44.
P53 gene replacement for cancer--interactions with DNA damaging agents.
Roth JA, Grammer SF, Swisher SG, Komaki R, Nemunaitis J, Merritt J, Meyn RE.
Department of Thoracic and Cardiovascular Surgery, The University of Texas, M. D. Anderson Cancer Center, Houston 77030, USA.
Clinical trials of p53 gene replacement have provided information that will be useful in the design of future gene therapy strategies. Direct intratumor injection has low toxicity and thus can be readily combined with existing treatments. Post-injection gene expression can be documented and occurs in the presence of an anti-adenovirus immune response. Importantly, this treatment can cause tumor regression or prolonged stabilization. Future research directions will include development of more efficient vectors, use of novel genes, and combined modality approaches. Unresectable tumors are a prominent problem in oncology, with proven therapies such as radiotherapy and chemotherapy controlling less than 20% of lung cancers. Based on the preclinical and clinical studies discussed, it now seems that these conventional therapies may provide renewed potential when used in conjunction with transfer of a functional p53 gene.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 11765069 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
13: EMBO J. 2001 Sep 3;20(17):4634-8.
Hsp70 interactions with the p53 tumour suppressor protein.
Zylicz M, King FW, Wawrzynow A.
Department of Molecular Biology, International Institute of Molecular and Cell Biology UNESCO, Warsaw 02-109, Poland. zylicz@iimcb.gov.pl
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 11532927 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
14: Semin Cancer Biol. 2001 Feb;11(1):23-30.
Role of T antigen interactions with p53 in tumorigenesis.
Pipas JM, Levine AJ.
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
SV40 induces neoplastic transformation by disabling several key cellular growth regulatory circuits. Among these are the Rb- and p53-families of tumor suppressors. The multifunctional, virus-encoded large T antigen blocks the function of both Rb and p53. Large T antigen uses multiple mechanisms to block p53 activity, and this action contributes to tumorigenesis, in part, by blocking p53-mediated growth suppression and apoptosis. Since the p53 pathway is inactivated in most human tumors, T antigen/p53 interactions offer a possible mechanism by which SV40 contributes to human cancer. Copyright 2001 Academic Press.
Publication Types:
Review
PMID: 11243896 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
15: Semin Cancer Biol. 2000 Dec;10(6):453-9.
Interactions between adenovirus proteins and the p53 pathway: the development of ONYX-015.
McCormick F.
Cancer Research Institute, UCSF Cancer Comprehensive Cancer Center, San Francisco, CA 94115, USA. mccormick@cc.ucsf.edu
dl1520 (ONYX-015) is an adenovirus mutant that lacks the E1b 55K gene. As a result it cannot neutralize p53. Therefore dl1520 should only grow in cells that lack p53, and should replicate selectively in cancer cells. However, there is no correlation between replication and p53 status, in cancer cells. This is for two reasons: (1) E1B 55K has additional functions, that are necessary in some tumor cells and not in others. (2) p53 function can be lost by alternative mechanisms such as loss of p14ARF. In normal cells, dl1520 induces p53, and is generally strongly attenuated for replication. ONYX-015 is currently being tested in clinical trials, and is a promising new therapeutic agent in cancer. Copyright 2000 Academic Press.
Publication Types:
Review
PMID: 11170867 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
16: J Pathol. 1999 Jan;187(1):8-18.
Molecular epidemiology of human cancer risk: gene-environment interactions and p53 mutation spectrum in human lung cancer.
Bennett WP, Hussain SP, Vahakangas KH, Khan MA, Shields PG, Harris CC.
Division of Human Genetics, City of Hope, National Medical Center, Duarte, CA, USA.
The p53 tumour suppressor gene is at the crossroads of a network of cellular pathways including cell cycle checkpoints, DNA repair, chromosomal segregation, and apoptosis. These pathways have evolved to maintain the stability of the genome during cellular stress from DNA damage, hypoxia, and activated oncogenes. The high frequency of p53 mutations in human cancer is a reflection of the importance of p53 involvement in this network of pathways during human carcinogenesis. An electronic database containing p53 mutations from more than 9000 cancers (http:/(/)www.iarc.fr/p53/homepage.html) can be used to generate hypotheses for further clinical, epidemiological, and laboratory investigations. For example, one can hypothesize that (a) p53 mutations vary in their pathobiological significance; (b) cellular content influences the selection of p53 mutations in clonally derived cancers; (c) the location and type of mutation within the p53 gene provide clues to functional domains in the gene product; and (d) the p53 mutation spectrum can be a molecular link between aetiological agents and human cancer. This review will focus on the role of p53 and cancer susceptibility genes in the molecular pathogenesis and epidemiology of human lung cancer.
Publication Types:
Review
PMID: 10341702 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
17: Anticancer Res. 1998 May-Jun;18(3A):1713-25.
Mutual interactions between p53 and growth factors in cancer.
Asschert JG, Vellenga E, De Jong S, de Vries EG.
Department of Internal Medicine, University Hospital Groningen, The Netherlands.
The function of p53 tumour suppressor protein is determined by various intrinsic properties of the protein. The effect of p53 DNA-binding, and protein-protein interactions are determined by the conformation of the protein. Thus, p53 fulfils its role in cell cycle control and the onset of apoptotic cell death, which is altered when the wild-type p53 (wt-p53) conformation is changed due to mutation. This review focuses on the communal interactions of wt- and mutant p53 (m-p53) with growth factors and shows that m-p53 affects different cell biological functions that determine the malignant behaviour of cells. P53, for instance, affects the response of cells to growth factors and growth factor-withdrawal. Furthermore, p53 is involved in the expression of several growth factor- and growth factor receptor genes. These data suggest that restoration of the wt-p53 phenotype in tumour cells with m-53 might not only affect cell cycle control and apoptotic mechanisms but could also reduce autocrine growth and restore sensitivity to physiological growth inhibitors.
Publication Types:
Review
PMID: 9673395 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
18: 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]
--------------------------------------------------------------------------------
19: FASEB J. 1993 Jul;7(10):866-71.
Interactions between SV40 large-tumor antigen and the growth suppressor proteins pRB and p53.
Ludlow JW.
University of Rochester Cancer Center, Division of Tumor Biology, New York.
The oncogenic property of simian virus 40 depends in large part on the function of the virus-coded T-antigen. Although the precise mechanism of how T functions during neoplastic transformation is not clear, some answers to this question may lie in our understanding the nature of the proteins found to complex with T. The cellular protein p53 is perhaps the most extensively studied protein in this regard. Recently, p53 was defined as a growth suppressor protein. At about this same time, T was found to complex with another cell growth suppressor protein, the product of the retinoblastoma susceptibility gene. It has since become apparent that complex formation between these proteins affects their individual growth-modulating activities. Quite often this alteration of activity correlates with an uncontrolled proliferative state of the cell. Thus, transformation by SV40 is thought to involve complex formation between the viral T oncoprotein and cellular growth suppressor proteins. This complex formation is believed to result in nullification of the growth suppressor protein properties, thus increasing the propensity of the cell toward uncontrolled growth, the hallmark of neoplastic transformation.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 8344486 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
20: Virology. 1990 Aug;177(2):419-26.
The p53 protein and its interactions with the oncogene products of the small DNA tumor viruses.
Levine AJ.
Department of Molecular Biology, Princeton University, New Jersey 08544-1014.
Publication Types:
Review
PMID: 2142553 [PubMed - indexed for MEDLINE]
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]
--------------------------------------------------------------------------------
2: Oncogene. 2007 Apr 2;26(15):2185-90.
Interactions of mutant p53 with DNA: guilt by association.
Kim E, Deppert W.
Translational Neuro-Oncology Group, Department of Neurosurgery, Georg-August-University of Goettingen, Robert-Koch-Strasse 40, Goettingen, Germany. ella.kim@med.uni-goettingen.de
Since the very early days of p53 research, the gain of oncogenic activities by some mutant p53 proteins had been suspected as an important factor contributing to cancer progression. Considerable progress towards understanding the biology of mutant p53 has been made during the last years, the quintessence being the realization that the impact of mutant p53 proteins on the transcriptome of a tumor cell is much more global than previously thought. The emerging role of mutant p53 proteins in coordinating oncogenic signaling and chromatin modifying activities reveals an until now unsuspected function of these proteins as important modifiers of the oncogenic transcriptional response. Notwithstanding the fact that the sequence-specific DNA binding activity of mutant p53 proteins is impaired, they are still able to associate with specific loci on DNA by utilizing different mechanisms. The ability to associate with DNA appears to be crucial for the master role of mutant p53 proteins in coordinating oncogenic transcriptional responses.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 17401427 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
3: Apoptosis. 2006 May;11(5):659-61.
p53 and Retinoblastoma protein (pRb): a complex network of interactions.
Godefroy N, Lemaire C, Mignotte B, Vayssière JL.
Laboratoire de Génétique et Biologie Cellulaire (CNRS UMR8159), Université de Versailles Saint-Quentin-en-Yvelines, 45 Avenue des Etats-Unis, 78035, Versailles Cedex, France.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16554964 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
4: Cell Death Differ. 2006 Jun;13(6):885-9.
The versatile interactions of p53 with DNA: when flexibility serves specificity.
Kim E, Deppert W.
Neuro-Oncology Research Group, Department of Neurosurgery, University of Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, D-23538 Luebeck, Germany.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16543936 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
5: J Nutr. 2004 Sep;134(9):2482S-2486S.
Diet-gene interactions in p53-deficient mice: insulin-like growth factor-1 as a mechanistic target.
Hursting SD, Lavigne JA, Berrigan D, Donehower LA, Davis BJ, Phang JM, Barrett JC, Perkins SN.
Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. hurstins@mail.nih.gov
Progress in cancer prevention research is being facilitated by the use of animal models displaying specific genetic susceptibilities for cancer, such as mice deficient in one (+/-) or both (-/-) alleles of the p53 tumor suppressor gene. Our lab, which focuses on nutrition (particularly energy balance/obesity) and molecular carcinogenesis, has shown in p53-/- mice that calorie restriction (CR) increases the latency of spontaneous tumor development (mostly lymphomas) approximately 75%, decreases serum insulin-like growth factor (IGF)-1 and leptin levels, and induces apoptosis in immature (lymphoma-susceptible) thymocytes. In heterozygous p53-deficient (p53+/-) mice, CR and a one day/wk fast each significantly delay spontaneous tumor development (a mix of lymphomas, sarcomas, and epithelial tumors) and decreases serum IGF-1 and leptin levels, even when begun late in life. We are presently comparing and combining CR and exercise (treadmill and running wheel) to further elucidate the relationships between energy balance, p53, and tumorigenesis in these models. Furthermore, we have capitalized on the susceptibility of p53+/- mice to chronic, low-dose aromatic amine-induced bladder carcinogenesis to develop a model for evaluating bladder cancer prevention approaches. Using this model, we have established that IGF-1 mediates many of the anti-cancer effects of CR. We are currently conducting oligonucleotide microarray studies to further characterize diet-gene interactions underlying the anti-cancer effects of CR and to determine which of the CR-responsive genes are IGF-1 dependent.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 15333746 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
6: Ann N Y Acad Sci. 2004 Jun;1024:54-71.
Physiological and pathological consequences of the interactions of the p53 tumor suppressor with the glucocorticoid, androgen, and estrogen receptors.
Sengupta S, Wasylyk B.
Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
The p53 tumor suppressor plays a key role in protection from the effects of different physiological stresses (DNA damage, hypoxia, transcriptional defects, etc.), and loss of its activity has dire consequences, such as cancer. Its activity is finely tuned through interactions with other important regulatory circuits in the cell. Recently, striking evidence has emerged for crosstalk with another class of important regulators, the steroid hormone receptors, and in particular the glucocorticoid (GR), androgen (AR), and estrogen (ER) receptors. These receptors are important in maintaining homeostasis in response to internal and external stresses (GR) and in the development, growth, and maintenance of the male and female reproductive systems (AR and ER, respectively). We review how p53 interacts closely with these receptors, to the extent that they share the same E3 ubiquitin ligase, the MDM2 oncoprotein. We discuss the different physiological contexts in which such interactions occur, and also how these interactions have been undermined in various pathological situations. We will describe future areas for research, with special emphasis on GR, and how certain common features, such as cytoplasmic anchoring of p53 by the receptors, may become targets for the development of therapeutic interventions. Given the importance of GR in inflammation, erythropoiesis, and autoimmune diseases, and the importance of AR and ER in prostate and breast cancer (respectively), the studies on p53 interactions with the steroid receptors will be an important domain in the near future.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
Review
PMID: 15265773 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
7: Trends Pharmacol Sci. 2004 Jul;25(7):343-6.
Small-molecule inhibitors of the p53 suppressor HDM2: have protein-protein interactions come of age as drug targets?
Fischer PM, Lane DP.
Cyclacel Limited, James Lindsay Place, Dundee DD1 5JJ, Scotland, UK. pfischer@cyclacel.com
Publication Types:
Review
PMID: 15219971 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
8: Cancer Biol Ther. 2004 Feb;3(2):156-61. Epub 2004 Feb 1.
The functional interactions between the p53 and MAPK signaling pathways.
Wu GS.
Program in Molecular Biology and Human Genetics, Karmanos Cancer Institute, Department of Pathology, Wayne State University School of Medicine, Room E216, The Prentis Building, 110 East Warren Avenue, Detroit, Michigan 48201, USA. wug@karmanos.org
The p53 tumor suppressor protein exerts its growth inhibitory activity by activating and interacting with diverse signaling pathways. As a downstream target, p53 protein is phosphorylated and activated by a number of protein kinases in response to stressful stimuli. As an upstream activator, activated p53 acts as a transcription factor to induce and/or suppress a number of genes whose expression leads to the activation of diverse signaling pathways. p53 protein can also interact with a number of proteins, resulting in an increase or decrease in p53 activity itself. The activation of p53 leads to many outcomes in cells, including cell cycle arrest and apoptosis. It has become clear that the p53 protein can functionally interact with the mitogen-activated protein kinase (MAPK) pathways, including the stress-activated protein kinase [SAPK/c-Jun N-terminal protein kinase (JNK)], the p38 mitogen-activated protein kinase (MAPK), and the extracellular signal related kinase (ERK). Upon exposure to stressful stimuli, MAP kinases phosphorylate and activate p53, leading to p53-mediated cellular responses. Recent studies have suggested a role of p53 as an upstream activator to regulate MAPK signaling via the transcriptional activation of members of the dual specificity phosphatase family. Because both the p53 and MAPK signaling pathways are altered in the majority of human tumors, understanding their functional interaction may provide new insights into the deregulated cell proliferation and survival that is characteristic of cancer.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 14764989 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
9: Biochem Biophys Res Commun. 2003 Dec 5;312(1):109-14.
Bacterial cupredoxin azurin and its interactions with the tumor suppressor protein p53.
Punj V, Das Gupta TK, Chakrabarty AM.
Department of Microbiology and Immunology, University of Illinois, College of Medicine, 835 South Wolcott Avenue, Chicago, IL 60612, USA.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 14630027 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
10: Biochem Cell Biol. 2003 Jun;81(3):141-50.
The complex interactions of p53 with target DNA: we learn as we go.
Kim E, Deppert W.
Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie, Universität Hamburg, Germany.
The most import biological function of the tumor suppressor p53 is that of a sequence-specific transactivator. In response to a variety of cellular stress stimuli, p53 induces the transcription of an ever-increasing number of target genes, leading to growth arrest and repair, or to apoptosis. Long considered as a "latent" DNA binder that requires prior activation by C-terminal modification, recent data provide strong evidence that the DNA binding activity of p53 is strongly dependent on structural features within the target DNA and is latent only if the target DNA lacks a certain structural signal code. In this review we discuss evidence for complex interactions of p53 with DNA, which are strongly dependent on the dynamics of DNA structure, especially in the context of chromatin. We provide a model of how this complexity may serve to achieve selectivity of target gene regulation by p53 and how DNA structure in the context of chromatin may serve to modulate p53 functions.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 12897847 [PubMed - indexed for MEDLINE]
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11: Methods Mol Med. 2003;74:43-59.
Molecular epidemiology of human cancer risk. Gene-environment interactions and p53 mutation spectrum in human lung cancer.
Vähäkangas K.
Department of Pharmacology and Toxicology, University of Kuopio, Finland.
Molecular epidemiology of cancer risk utilizes knowledge of both the genetic changes in cancer and the current hypothesis of chemical carcinogenesis when selecting possible markers for individual susceptibility, early disease, and biologically significant exposure. Polymorphisms of drug-metabolizing enzymes, especially CYP enzymes, and mutations in the p53 tumor-suppressor gene have been in the center of interest for the past decade. Both have shown promise, CYP polymorphisms as markers for individual susceptibility and p53 mutation spectrum at population level for specific exposure. However, it is probable that very few markers, if any, are sufficient alone. Future challenges for molecular epidemiology in the lung cancer field include pursuing ethically the best performance in applying that knowledge, in addition to the development of reliable and well-validated markers.
Publication Types:
Review
PMID: 12415685 [PubMed - indexed for MEDLINE]
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12: Acta Oncol. 2001;40(6):739-44.
P53 gene replacement for cancer--interactions with DNA damaging agents.
Roth JA, Grammer SF, Swisher SG, Komaki R, Nemunaitis J, Merritt J, Meyn RE.
Department of Thoracic and Cardiovascular Surgery, The University of Texas, M. D. Anderson Cancer Center, Houston 77030, USA.
Clinical trials of p53 gene replacement have provided information that will be useful in the design of future gene therapy strategies. Direct intratumor injection has low toxicity and thus can be readily combined with existing treatments. Post-injection gene expression can be documented and occurs in the presence of an anti-adenovirus immune response. Importantly, this treatment can cause tumor regression or prolonged stabilization. Future research directions will include development of more efficient vectors, use of novel genes, and combined modality approaches. Unresectable tumors are a prominent problem in oncology, with proven therapies such as radiotherapy and chemotherapy controlling less than 20% of lung cancers. Based on the preclinical and clinical studies discussed, it now seems that these conventional therapies may provide renewed potential when used in conjunction with transfer of a functional p53 gene.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 11765069 [PubMed - indexed for MEDLINE]
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13: EMBO J. 2001 Sep 3;20(17):4634-8.
Hsp70 interactions with the p53 tumour suppressor protein.
Zylicz M, King FW, Wawrzynow A.
Department of Molecular Biology, International Institute of Molecular and Cell Biology UNESCO, Warsaw 02-109, Poland. zylicz@iimcb.gov.pl
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 11532927 [PubMed - indexed for MEDLINE]
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14: Semin Cancer Biol. 2001 Feb;11(1):23-30.
Role of T antigen interactions with p53 in tumorigenesis.
Pipas JM, Levine AJ.
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
SV40 induces neoplastic transformation by disabling several key cellular growth regulatory circuits. Among these are the Rb- and p53-families of tumor suppressors. The multifunctional, virus-encoded large T antigen blocks the function of both Rb and p53. Large T antigen uses multiple mechanisms to block p53 activity, and this action contributes to tumorigenesis, in part, by blocking p53-mediated growth suppression and apoptosis. Since the p53 pathway is inactivated in most human tumors, T antigen/p53 interactions offer a possible mechanism by which SV40 contributes to human cancer. Copyright 2001 Academic Press.
Publication Types:
Review
PMID: 11243896 [PubMed - indexed for MEDLINE]
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15: Semin Cancer Biol. 2000 Dec;10(6):453-9.
Interactions between adenovirus proteins and the p53 pathway: the development of ONYX-015.
McCormick F.
Cancer Research Institute, UCSF Cancer Comprehensive Cancer Center, San Francisco, CA 94115, USA. mccormick@cc.ucsf.edu
dl1520 (ONYX-015) is an adenovirus mutant that lacks the E1b 55K gene. As a result it cannot neutralize p53. Therefore dl1520 should only grow in cells that lack p53, and should replicate selectively in cancer cells. However, there is no correlation between replication and p53 status, in cancer cells. This is for two reasons: (1) E1B 55K has additional functions, that are necessary in some tumor cells and not in others. (2) p53 function can be lost by alternative mechanisms such as loss of p14ARF. In normal cells, dl1520 induces p53, and is generally strongly attenuated for replication. ONYX-015 is currently being tested in clinical trials, and is a promising new therapeutic agent in cancer. Copyright 2000 Academic Press.
Publication Types:
Review
PMID: 11170867 [PubMed - indexed for MEDLINE]
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16: J Pathol. 1999 Jan;187(1):8-18.
Molecular epidemiology of human cancer risk: gene-environment interactions and p53 mutation spectrum in human lung cancer.
Bennett WP, Hussain SP, Vahakangas KH, Khan MA, Shields PG, Harris CC.
Division of Human Genetics, City of Hope, National Medical Center, Duarte, CA, USA.
The p53 tumour suppressor gene is at the crossroads of a network of cellular pathways including cell cycle checkpoints, DNA repair, chromosomal segregation, and apoptosis. These pathways have evolved to maintain the stability of the genome during cellular stress from DNA damage, hypoxia, and activated oncogenes. The high frequency of p53 mutations in human cancer is a reflection of the importance of p53 involvement in this network of pathways during human carcinogenesis. An electronic database containing p53 mutations from more than 9000 cancers (http:/(/)www.iarc.fr/p53/homepage.html) can be used to generate hypotheses for further clinical, epidemiological, and laboratory investigations. For example, one can hypothesize that (a) p53 mutations vary in their pathobiological significance; (b) cellular content influences the selection of p53 mutations in clonally derived cancers; (c) the location and type of mutation within the p53 gene provide clues to functional domains in the gene product; and (d) the p53 mutation spectrum can be a molecular link between aetiological agents and human cancer. This review will focus on the role of p53 and cancer susceptibility genes in the molecular pathogenesis and epidemiology of human lung cancer.
Publication Types:
Review
PMID: 10341702 [PubMed - indexed for MEDLINE]
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17: Anticancer Res. 1998 May-Jun;18(3A):1713-25.
Mutual interactions between p53 and growth factors in cancer.
Asschert JG, Vellenga E, De Jong S, de Vries EG.
Department of Internal Medicine, University Hospital Groningen, The Netherlands.
The function of p53 tumour suppressor protein is determined by various intrinsic properties of the protein. The effect of p53 DNA-binding, and protein-protein interactions are determined by the conformation of the protein. Thus, p53 fulfils its role in cell cycle control and the onset of apoptotic cell death, which is altered when the wild-type p53 (wt-p53) conformation is changed due to mutation. This review focuses on the communal interactions of wt- and mutant p53 (m-p53) with growth factors and shows that m-p53 affects different cell biological functions that determine the malignant behaviour of cells. P53, for instance, affects the response of cells to growth factors and growth factor-withdrawal. Furthermore, p53 is involved in the expression of several growth factor- and growth factor receptor genes. These data suggest that restoration of the wt-p53 phenotype in tumour cells with m-53 might not only affect cell cycle control and apoptotic mechanisms but could also reduce autocrine growth and restore sensitivity to physiological growth inhibitors.
Publication Types:
Review
PMID: 9673395 [PubMed - indexed for MEDLINE]
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18: 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]
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19: FASEB J. 1993 Jul;7(10):866-71.
Interactions between SV40 large-tumor antigen and the growth suppressor proteins pRB and p53.
Ludlow JW.
University of Rochester Cancer Center, Division of Tumor Biology, New York.
The oncogenic property of simian virus 40 depends in large part on the function of the virus-coded T-antigen. Although the precise mechanism of how T functions during neoplastic transformation is not clear, some answers to this question may lie in our understanding the nature of the proteins found to complex with T. The cellular protein p53 is perhaps the most extensively studied protein in this regard. Recently, p53 was defined as a growth suppressor protein. At about this same time, T was found to complex with another cell growth suppressor protein, the product of the retinoblastoma susceptibility gene. It has since become apparent that complex formation between these proteins affects their individual growth-modulating activities. Quite often this alteration of activity correlates with an uncontrolled proliferative state of the cell. Thus, transformation by SV40 is thought to involve complex formation between the viral T oncoprotein and cellular growth suppressor proteins. This complex formation is believed to result in nullification of the growth suppressor protein properties, thus increasing the propensity of the cell toward uncontrolled growth, the hallmark of neoplastic transformation.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 8344486 [PubMed - indexed for MEDLINE]
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20: Virology. 1990 Aug;177(2):419-26.
The p53 protein and its interactions with the oncogene products of the small DNA tumor viruses.
Levine AJ.
Department of Molecular Biology, Princeton University, New Jersey 08544-1014.
Publication Types:
Review
PMID: 2142553 [PubMed - indexed for MEDLINE]
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