p53 mutant mice that display early ageing-associated phenotypes

  title={p53 mutant mice that display early ageing-associated phenotypes},
  author={Stuart D. Tyner and Sundaresan Venkatachalam and Jene Choi and Stephen N. Jones and Nader Ghebranious and Herbert Igelmann and Xiongbin Lu and Gabrielle Soron and Benjamin Cooper and Cory F Brayton and Sang Hee Park and Timothy C. Thompson and G{\'e}rard Karsenty and Allan Bradley and Lawrence A. Donehower},
The p53 tumour suppressor is activated by numerous stressors to induce apoptosis, cell cycle arrest, or senescence. To study the biological effects of altered p53 function, we generated mice with a deletion mutation in the first six exons of the p53 gene that express a truncated RNA capable of encoding a carboxy-terminal p53 fragment. This mutation confers phenotypes consistent with activated p53 rather than inactivated p53. Mutant (p53+/m) mice exhibit enhanced resistance to spontaneous… 
Hyperactive p53 leads to age-related phenotypes in mice model
It is concluded that hyperactivity of p53 through T21S23/D mutation leads to age-related phenotypes in mice models that exhibit reduced lifespan and cell cycle arrest in super-active p53 mice models.
Does p53 affect organismal aging?
These p53 mutants exhibit increased cancer resistance, yet have a shortened longevity and display a number of early aging‐associated phenotypes, suggesting a role for p53 in the aging process.
Mdm2-p53 signaling regulates epidermal stem cell senescence and premature aging phenotypes in mouse skin.
A polymorphism in the tumor suppressor p53 affects aging and longevity in mouse models
Direct genetic evidence is provided demonstrating that p53 codon 72 SNP directly impacts aging and longevity, which supports a role of p53 in regulation of longevity.
Timed Somatic Deletion of p53 in Mice Reveals Age-Associated Differences in Tumor Progression
It is indicated that sustained p53 anti-oncogenic function acts as a final or near final line of defense preventing progression of oncogenically activated cells to malignant tumors.
Complicating the role of p53 in aging
It is shown that there are 24 genes deleted in the p53+/m mouse model, complicating the role of p53 in aging and raising the possibility that the phenotypes while resembling ‘premature aging‐like’ symptoms, may not be related to the physiological changes seen during normal aging processes.
'Super p53' mice exhibit enhanced DNA damage response, are tumor resistant and age normally
The generation and characterization of mice carrying supernumerary copies of the p53 gene in the form of large genomic transgenes are reported, proving that cancer resistance can be enhanced by a simple genetic modification and in the absence of undesirable effects.
Senescence, aging, and malignant transformation mediated by p53 in mice lacking the Brca1 full-length isoform.
In vivo evidence is shown that the absence of the Brca1 full-length isoform causes senescence in mutant embryos and cultured cells as well as aging and tumorigenesis in adult mice, providing the first in vivo evidence that links cellsenescence to aging due to impaired function of Brca2 at the expense of tumorigenisation.
In vivo analysis of p53 tumor suppressor function using genetically engineered mouse models.
Studying p53 mouse models has established that both p53-driven cell-cycle arrest and apoptosis responses contribute to tumor suppression and that activation of p53 by oncogenic stress imposes an important barrier to tumorigenesis, suggesting that p53 restoration in human cancer patients may be a promising therapeutic strategy.


Analysis of ku80-Mutant Mice and Cells with Deficient Levels of p53
Data show that replicative senescence is caused by a p53-dependent cell cycle response to damaged DNA inku80 −/− cells and that p53 is essential for preventing very early onset of pro-B-cell lymphoma inku 80 −/+ mice.
Escape from senescence in human diploid fibroblasts induced directly by mutant p53.
It is concluded that a key tumour-limiting function of wild-type p53 is to mediate growth arrest after a given number of cell divisions, in agreement with data implicating a p53-regulated gene, WAF-1/sdi-1, in cellular senescence.
Tumor spectrum analysis in p53-mutant mice
Retention of wild‐type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation
It is indicated that loss of both p53 alleles is not a prerequisite for tumor formation and that mere reduction in p53 levels may be sufficient to promote tumorigenesis.
Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain
We demonstrate here that synthetic 22-mer peptide 46, corresponding to the car boxy-terminal amino acid residues 361–382 of p53, can activate specific DNA binding of wild-type p53 in vitro and can
Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours
Observations indicate that a normal p53 gene is dispensable for embryonic development, that its absence predisposes the animal to neoplastic disease, and that an oncogenic mutant form of p53 is not obligatory for the genesis of many types of tumours.
Tumour incidence, spectrum and ploidy in mice with a large deletion in the p53 gene.
A large deletion within the p53 gene is generated, consistent with the concept that p53 acts as a tumour suppressor by preventing the propagation of DNA damage to daughter cells.
Increased activity of p53 in senescing fibroblasts.
Examination of the expression and activity of p53 during replicative aging provides evidence for the activation of a protein involved in the control of cell cycle checkpoints during cellular aging, in the absence of increased expression.