Journal ArticleDOI
The codon 72 polymorphic variants of p53 have markedly different apoptotic potential.
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TLDR
It is found that in cell lines containing inducible versions of alleles encoding the Pro72 and Arg72 variants, and in cells with endogenous p53, the Arg72 variant induces apoptosis markedly better than does the Pro 72 variant.Abstract:
The gene TP53, encoding p53, has a common sequence polymorphism that results in either proline or arginine at amino-acid position 72. This polymorphism occurs in the proline-rich domain of p53, which is necessary for the protein to fully induce apoptosis. We found that in cell lines containing inducible versions of alleles encoding the Pro72 and Arg72 variants, and in cells with endogenous p53, the Arg72 variant induces apoptosis markedly better than does the Pro72 variant. Our data indicate that at least one source of this enhanced apoptotic potential is the greater ability of the Arg72 variant to localize to the mitochondria; this localization is accompanied by release of cytochrome c into the cytosol. These data indicate that the two polymorphic variants of p53 are functionally distinct, and these differences may influence cancer risk or treatment.read more
Citations
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Journal ArticleDOI
DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome
Timothy J. Ley,Elaine R. Mardis,Li Ding,Bob Fulton,Michael D. McLellan,Ken Chen,David J. Dooling,Brian H. Dunford-Shore,Sean McGrath,Matthew T. Hickenbotham,Lisa Cook,Rachel Abbott,David E. Larson,Daniel C. Koboldt,Craig Pohl,Scott M. Smith,Amy Hawkins,Scott Abbott,Devin P. Locke,LaDeana W. Hillier,Tracie L. Miner,Lucinda Fulton,Vincent Magrini,Todd Wylie,Jarret Glasscock,Joshua J. Conyers,Nathan Sander,Xiaoqi Shi,John R. Osborne,Patrick Minx,David Gordon,Asif T. Chinwalla,Yu Zhao,Rhonda E. Ries,Jacqueline E. Payton,Peter Westervelt,Michael H. Tomasson,Mark A. Watson,Jack Baty,Jennifer Ivanovich,Sharon Heath,William D. Shannon,Rakesh Nagarajan,Matthew J. Walter,Daniel C. Link,Timothy A. Graubert,John F. DiPersio,Richard K. Wilson +47 more
TL;DR: This study establishes whole-genome sequencing as an unbiased method for discovering cancer-initiating mutations in previously unidentified genes that may respond to targeted therapies.
Journal ArticleDOI
Puma is an essential mediator of p53-dependent and -independent apoptotic pathways
John R. Jeffers,Evan Parganas,Evan Parganas,Youngsoo Lee,Chunying Yang,Jinling Wang,Jennifer Brennan,Kirsteen H. Maclean,Jia-wen Han,Thomas Chittenden,James N. Ihle,James N. Ihle,Peter J. McKinnon,John L. Cleveland,Gerard P. Zambetti +14 more
TL;DR: It is reported that Puma is essential for hematopoietic cell death triggered by ionizing radiation, deregulated c-Myc expression, and cytokine withdrawal, and required for IR-induced death throughout the developing nervous system and accounts for nearly all of the apoptotic activity attributed to p53 under these conditions.
Journal ArticleDOI
TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes
TL;DR: It is shown that intrinsic mutagenicity rates, loss of transactivation activities, and to a lesser extent, dominant-negative activities are the main driving forces that determine TP53 mutation patterns and influence tumor phenotype.
Journal ArticleDOI
Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex
TL;DR: It is shown that, after cell stress, p53 interacts with the pro-apoptotic mitochondrial membrane protein Bak, which is consistent with a model in which p53 and Mcl1 have opposing effects on mitochondrial apoptosis by interacting with, and modulating the activity of, the death effector Bak.
Journal ArticleDOI
The P53 pathway: what questions remain to be explored?
TL;DR: The p53 pathway is composed of hundreds of genes and their products that respond to a wide variety of stress signals that play a role in protection from cancers, therapy and integrating the homeostatic mechanisms of stress management and fidelity in a cell and organism.
References
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Journal ArticleDOI
p53 polymorphisms and haplotypes in different ethnic groups.
TL;DR: The present results indicate that extended haplotypes would be more informative in studies of population differences and associations between p53 germline mutations and cancer.
Journal ArticleDOI
Proteolytic Cleavage of the mdm2 Oncoprotein during Apoptosis
TL;DR: Evidence is presented that the mDM2 oncoprotein is cleaved by an interleukin 1β-converting enzyme-like protease (caspase) during p53-mediated apoptosis, suggesting that regulation by caspase cleavage during apoptosis is an important feature of mdm2.
Journal ArticleDOI
P53 polymorphisms and haplotypes in lung cancer
R. Birgander,Anders Själander,Agneta Rannug,A.-K. Alexandrie,M. Ingelman–Sundberg,Janeric Seidegård,Göran Tornling,Gunhild Beckman,Lars Beckman +8 more
TL;DR: In this paper, a reanalysis of the data by Kawajiri et al. revealed no significant difference between patients and controls with respect to allele frequencies, and the increased frequency of BstU I 1-1 homozygotes was mostly ascribed to a deviation from the Hardy-Weinberg equilibrium.
Journal ArticleDOI
Determination of the allelic frequencies of an L-myc and a p53 polymorphism in human lung cancer.
Ainsley Weston,Helen M. Ling-Cawley,Neil E. Caporaso,Elise D. Bowman,Robert N. Hoover,Benjamin F. Trump,Curtis C. Harris +6 more
TL;DR: Results from a study comparing lung cancer cases with chronic obstructive pulmonary disease controls found no association was found between these RFLPs and disease status.
Journal ArticleDOI
p53 codon 72 polymorphism and risk of cervical cancer.
José Manuel Ojeda,Sandra Ampuero,Patricio Rojas,Rodrigo Prado,Jorge E. Allende,Sara A. Barton,Ranajit Chakraborty,Francisco Rothhammer +7 more
TL;DR: It is concluded that this distribution most likely represents ancient human dispersal routes and rejected previous hypotheses about the world distribution of the p53 codon 72 polymorphism.