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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Lack of correlation between p53-dependent transcriptional activity and the ability to induce apoptosis among 179 mutant p53s.
TL;DR: It is suggested that transactivation-dependent apoptosis does not always play a major role in p53- dependent apoptosis, indirectly supporting the importance role of the trans activation-independent mechanism.
Journal Article
Retention of the p53 codon 72 arginine allele is associated with a reduction of disease-free and overall survival in arginine/proline heterozygous breast cancer patients.
Massimiliano Bonafè,Claudio Ceccarelli,Fulvia Farabegoli,Donatella Santini,Mario Taffurelli,Cristiana Barbi,Erika Marzi,Chiara Trapassi,Gianluca Storci,Fabiola Olivieri,Claudio Franceschi +10 more
TL;DR: It is found that the retention of the p53 codon 72 arginine allele in the tumor tissue of proline/arginine heterozygous breast cancer patients is associated with statistically significant reduced disease-free and overall survivals.
Journal ArticleDOI
MDM4 (MDMX) localizes at the mitochondria and facilitates the p53-mediated intrinsic-apoptotic pathway
Francesca Mancini,Francesca Mancini,Giusy Di Conza,Giusy Di Conza,Marsha Pellegrino,Cinzia Rinaldo,Andrea Prodosmo,Simona Giglio,Simona Giglio,Igea D'Agnano,Fulvio Florenzano,Lara Felicioni,Fiamma Buttitta,Antonio Marchetti,Ada Sacchi,Alfredo Pontecorvi,Silvia Soddu,Fabiola Moretti +17 more
TL;DR: It is shown that MDM4 stably localizes at the mitochondria, in which it facilitates mitochondrial localization of p53 phosphorylated at Ser46 (p53Ser46P) and promotes binding between p53Ser 46P and BCL2, release of cytochrome C and apoptosis.
Journal ArticleDOI
Mitochondrially Targeted p53 Has Tumor Suppressor Activities In vivo
TL;DR: In vivo data on the direct mitochondrial apoptotic p53 program lays the groundwork to further investigate its efficacy and safety and to address its possible therapeutic value in the future.
Journal ArticleDOI
Genes, ageing and longevity in humans: Problems, advantages and perspectives
Stefano Salvioli,Fabiola Olivieri,Francesca Marchegiani,Maurizio Cardelli,Aurelia Santoro,Elena Bellavista,Michele Mishto,Laura Invidia,Miriam Capri,Silvana Valensin,Federica Sevini,Elisa Cevenini,Laura Celani,Francesco Lescai,Efstathios S. Gonos,Calogero Caruso,Giuseppe Paolisso,G. De Benedictis,Daniela Monti,Claudio Franceschi +19 more
TL;DR: New approaches are urgently needed to overcome the limits of traditional association studies performed on a limited number of polymorphisms in order to make substantial progress to disentangle the genetics of a trait as complex as human longevity.
References
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Journal ArticleDOI
WAF1, a potential mediator of p53 tumor suppression
Wafik S. El-Deiry,Takashi Tokino,Victor E. Velculescu,Daniel B. Levy,Ramon Parsons,Jeffrey M. Trent,D Lin,W. Edward Mercer,Kenneth W. Kinzler,Bert Vogelstein +9 more
TL;DR: A gene is identified, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line and that could be an important mediator of p53-dependent tumor growth suppression.
Journal ArticleDOI
Mice Lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control
Chu-Xia Deng,Chu-Xia Deng,Pumin Zhang,J. Wade Harper,Stephen J. Elledge,Stephen J. Elledge,Philip Leder,Philip Leder +7 more
TL;DR: The results establish the role of p21CIP1/WAF1 in the G1 checkpoint, but suggest that the anti-apoptotic and theAnti-oncogenic effects of p53 are more complex.
Journal ArticleDOI
Protein regulation by monoubiquitin
TL;DR: Multi-ubiquitin chains at least four subunits long are required for efficient recognition and degradation of ubiquitylated proteins by the proteasome, but other functions of ubiquitin have been discovered that do not involve the protease.
Journal ArticleDOI
Role of a p53 polymorphism in the development of human papillomavirus-associated cancer.
Alan Storey,Miranda Thomas,Ann Kalita,Catherine A. Harwood,Daniela Gardiol,Fiamma Mantovani,Judith Breuer,Irene M. Leigh,Greg Matlashewski,Lawrence Banks +9 more
TL;DR: Allelic analysis of patients with HPV-associated tumours revealed a striking overrepresentation of homozygous arginine-72 p53 compared with the normal population, which indicated that individuals homozygously for arginin 72 are about seven times more susceptible to HPV- associated tumorigenesis than heterozygotes.
Journal ArticleDOI
Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling
TL;DR: This work proposes a model where p53 can contribute to apoptosis by direct signaling at the mitochondria, thereby amplifying the transcription-dependent apoptosis of p53.